Carlos Cepeda - Academia.edu (original) (raw)

Papers by Carlos Cepeda

Research paper thumbnail of Increased GABAergic function in mouse models of Huntington's disease: Reversal by BDNF

Journal of Neuroscience Research, 2004

Huntington&am... more Huntington's disease (HD) is characterized by loss of striatal gamma-aminobutyric acid (GABA)ergic medium-sized spiny projection neurons (MSSNs), whereas some classes of striatal interneurons are relatively spared. Striatal interneurons provide most of the inhibitory synaptic input to MSSNs and use GABA as their neurotransmitter. We reported previously alterations in glutamatergic synaptic activity in the R6/2 and R6/1 mouse models of HD. In the present study, we used whole-cell voltage clamp recordings to examine GABAergic synaptic currents in MSSNs from striatal slices in these two mouse models compared to those in age-matched control littermates. The frequency of spontaneous GABAergic synaptic currents was increased significantly in MSSNs from R6/2 transgenics starting around 5-7 weeks (when the overt behavioral phenotype begins) and continuing in 9-14-week-old mice. A similar increase was observed in 12-15-month-old R6/1 transgenics. Bath application of brain-derived neurotrophic factor, which is downregulated in HD, significantly reduced the frequency of spontaneous GABAergic synaptic currents in MSSNs from R6/2 but not control mice at 9-14 weeks. Increased GABA current densities also occurred in acutely isolated MSSNs from R6/2 animals. Immunofluorescence demonstrated increased expression of the ubiquitous alpha1 subunit of GABA(A) receptors in MSSNs from R6/2 animals. These results indicate that increases in spontaneous GABAergic synaptic currents and postsynaptic receptor function occur in parallel to progressive decreases in glutamatergic inputs to MSSNs. In conjunction, both changes will severely alter striatal outputs to target areas involved in the control of movement.

Research paper thumbnail of Pacemaker GABA synaptic activity may contribute to network synchronization in pediatric cortical dysplasia

Spontaneous pacemaker γ-aminobutyric acid (GABA) receptor-mediated synaptic activity (PGA) occurs... more Spontaneous pacemaker γ-aminobutyric acid (GABA) receptor-mediated synaptic activity (PGA) occurs in a subset of tissue samples from pediatric epilepsy surgery patients. In the present study, based on single-cell electrophysiological recordings from 120 cases, we describe the etiologies, cell types, and primary electrophysiological features of PGA. Cells displaying PGA occurred more frequently in the areas of greatest anatomical abnormality in cases of focal cortical dysplasia (CD), often associated with hemimegalencephaly (HME), and only rarely in non-CD etiologies. PGA was characterized by rhythmic synaptic events (5-10Hz) and was observed in normal-like, dysmorphic cytomegalic, and immature pyramidal neurons. PGA was action potential-dependent, mediated by GABAA receptors, and unaffected by antagonism of glutamate receptors. We propose that PGA is a unique electrophysiological characteristic associated with CD and HME. It could represent an abnormal signal that may contribute to epileptogenesis in malformed postnatal cortex by facilitating pyramidal neuron synchrony.

Research paper thumbnail of Neurons Recorded from Pediatric Epilepsy Surgery Patients with Cortical Dysplasia

Epilepsia, 2000

Purpose: Cortical dysplasia (CD) is a common pathological substrate in patients with early-onset ... more Purpose: Cortical dysplasia (CD) is a common pathological substrate in patients with early-onset childhood epilepsy. In CD tissue, little is known about the mechanisms responsible for cellular hyperexcitability. In this study, we report initial electrophysiological and morphological observations from normal and dysmorphic cells in pediatric CD patients.

Research paper thumbnail of NMDA Receptor Alterations in Neurons from Pediatric Cortical Dysplasia Tissue

Cerebral Cortex, 2004

The subunit composition of glutamate receptors affects their functional properties, and could con... more The subunit composition of glutamate receptors affects their functional properties, and could contribute to abnormal electrophysiology in pediatric cortical dysplasia (CD). We examined electrophysiological responses and subunit assembly of N-methyl-D-aspartate (NMDA) receptors in acutely dissociated normal-appearing pyramidal and cytomegalic neurons from CD tissue and normal-appearing pyramidal neurons from non-CD tissue. In most cytomegalic and ∼30% of normal-appearing pyramidal neurons from CD tissue, NMDA currents showed decreased Mg 2+ sensitivity compared with neurons from non-CD tissue. Ifenprodil had less effect in CD compared with non-CD neurons, indicating a functional loss of NR2B subunits. NMDA-evoked current density was decreased in cytomegalic compared with normal-appearing neurons. Single-cell reverse transcriptase polymerase chain reaction showed that all non-CD neurons expressed NR2B subunit mRNA. By comparison, 22% of pyramidal neurons in CD tissue lacked NR2B mRNA. Immunofluorescence showed a decrease in NR2B subunit expression in cytomegalic neurons and a subset of normal-appearing pyramidal neurons from CD tissue. Taken together, these results demonstrate the presence of NMDA receptors with altered subunit composition and Mg 2+ sensitivity that could contribute to functional abnormalities in CD.

Research paper thumbnail of Pediatric Cortical Dysplasia: Correlations between Neuroimaging, Electrophysiology and Location of Cytomegalic Neurons and Balloon Cells and Glutamate/GABA Synaptic Circuits

Developmental Neuroscience, 2005

Seizures in cortical dysplasia (CD) could be from cytomegalic neurons and balloon cells acting as... more Seizures in cortical dysplasia (CD) could be from cytomegalic neurons and balloon cells acting as epileptic 'pacemakers', or abnormal neurotransmission. This study examined these hypotheses using in vitro electrophysiological techniques to determine intrinsic membrane properties and spontaneous glutamatergic and GABAergic synaptic activity for normal-pyramidal neurons, cytomegalic neurons and balloon cells from 67 neocortical sites originating from 43 CD patients (ages 0.2-14 years). Magnetic resonance imaging (MRI), 18 fluoro-2-deoxyglucose positron emission tomography (FDG-PET) and electrocorticography graded cortical sample sites from least to worst CD abnormality. Results found that cytomegalic neurons and balloon cells were observed more frequently in areas of severe CD compared with mild or normal CD regions as assessed by FDG-PET/MRI. Cytomegalic neurons (but not balloon cells) correlated with the worst electrocorticography scores. Electrophysiological recordings demonstrated that cytomegalic and normalpyramidal neurons displayed similar firing properties without intrinsic bursting. By contrast, balloon cells were electrically silent. Normal-pyramidal and cytomegalic neurons displayed decreased spontaneous glutamatergic synaptic activity in areas of severe FDG-PET/MRI abnormalities compared with normal regions, while GABAergic activity was unaltered. In CD, these findings indicate that cytomegalic neurons (but not balloon cells) might contribute to epileptogenesis, but are not likely to be 'pacemaker' cells capable of spontaneous paroxysmal depolarizations. Furthermore, there was more GABA relative to glutamate synaptic neurotransmission in areas of severe CD. Thus, in CD tissue alternate mechanisms of epileptogenesis should be considered, and we suggest that GABAergic synaptic circuits interacting with cytomegalic and normal-pyramidal neurons with immature receptor properties might contribute to seizure generation.

Research paper thumbnail of Human Cortical Dysplasia and Epilepsy: An Ontogenetic Hypothesis Based on Volumetric MRI and NeuN Neuronal Density and Size Measurements

Cerebral Cortex, 2004

In epilepsy patients with cortical dysplasia (CD), this study determined the probable ontogenetic... more In epilepsy patients with cortical dysplasia (CD), this study determined the probable ontogenetic timing of pathogenesis based on the number, location and appearance of neurons. Magnetic resonance imaging (MRI) determined gray and white matter volumes of affected and nonaffected cerebral hemispheres, and gray and white matter neuronalnuclear protein (NeuN) densities and sizes were assessed in epilepsy surgery patients (0.2--38 years) with CD (n 5 25) and non-CD etiologies (n 5 14), and compared with autopsy cases (n 5 13; 0--33 years). Pathology group, seizure type and age at surgery were compared against MRI and NeuN data. CD patients demonstrated increased MRI cerebral (3%) and gray matter (8%) volumes of the affected compared with non-affected cerebral hemisphere, and increased layer 1 (131%), upper cortical (9--23%) and white matter (28--77%) NeuN densities compared with autopsy cases. Non-CD cases showed decreased cerebral volumes of the affected hemisphere (14--18%) without changes in NeuN densities. Compared with autopsy cases, in CD and non-CD patients, cortical neurons were hypertrophied. Patients with a history of infantile spasms had a 40% increase in the size of layer 1 neurons compared with cases without spasms. By age, regardless of pathology group, there were logarithmic increases in MRI cerebral and white matter volumes, logarithmic increases in the size of lower gray and superficial white matter neurons, and logarithmic decreases in gray and white matter neuronal densities. These results support the concept that there were more neurons than expected in layer 1, gray, and white matter of CD patients compared with non-CD and autopsy cases. In addition, the location and appearance of neurons are consistent with the hypothesis that CD is the consequence of abnormalities occurring late in corticoneurogenesis that involve excessive neurogenesis with retention of pre-plate cells in the molecular layer and subplate regions.

Research paper thumbnail of Dopamine Enhancement of NMDA Currents in Dissociated Medium-Sized Striatal Neurons: Role of D1 Receptors and DARPP-32

Dopamine (DA), via activation of D1 receptors, enhances N -methyl- D -aspartate (NMDA)-evoked res... more Dopamine (DA), via activation of D1
receptors, enhances
N
-methyl-
D
-aspartate (NMDA)-evoked responses
in striatal neurons. The present investigation examined further the
properties of this enhancement and the potential mechanisms by
which this enhancement might be effected. Dissociated medium-sized
striatal neurons were obtained from intact rats and mice or mutant
mice lacking the DA and cyclic adenosine 3
,5
monophosphate
(cAMP)-regulated phosphoprotein of
M
R
32,000 (DARPP-32).
NMDA (10 –1,000
M) induced inward currents in all neurons. In
acutely dissociated neurons from intact rats or mice, activation of D1
receptors with the selective agonist, SKF 81297, produced a dose-
dependent enhancement of NMDA currents. This enhancement was
reduced by the selective D1 receptor antagonist SKF 83566. Quinpi-
role, a D2 receptor agonist alone, produced small reductions of
NMDA currents. However, it consistently and significantly reduced
the enhancement of NMDA currents by D1 agonists. In dissociated
striatal neurons, in conditions that minimized the contributions of
voltage-gated Ca
2
conductances, the D1-induced potentiation was
not altered by blockade of L-type voltage-gated Ca
2
conductances in
contrast to results in slices. The DARPP-32 signaling pathway has an
important role in D1 modulation of NMDA currents. In mice lacking
DARPP-32, the enhancement was significantly reduced. Furthermore,
okadaic acid, a protein phosphatase 1 (PP-1) inhibitor, increased
D1-induced potentiation, suggesting that constitutively active PP-1
attenuates D1-induced potentiation. Finally, activation of D1 recep-
tors produced differential effects on NMDA and gamma aminobutyric
acid (GABA)-induced currents in the same cells, enhancing NMDA
currents and inhibiting GABA currents. Thus simultaneous activation
of D1, NMDA, and GABA receptors could predispose medium-sized
spiny neurons toward excitation. Taken together, the present findings
indicate that the unique potentiation of NMDA receptor function by
activation of the D1 receptor signaling cascade can be controlled by
multiple mechanisms and has major influences on neuronal function

Research paper thumbnail of Electrophysiological and Morphological Analyses of Cortical Neurons Obtained from Children with Catastrophic Epilepsy: Dopamine Receptor Modulation of Glutamatergic Responses

Developmental Neuroscience, 1999

The present study examined the electrophysiological effects produced by activation of specific do... more The present study examined the electrophysiological effects produced by activation of specific dopamine (DA) receptors and the distribution of DA receptor subtypes and glutamate receptor subunits [N-methyl-D-aspartate (NMDAR1) and GluR1] in cortical tissue samples obtained from children (ages 3 months to 16 years) undergoing epilepsy surgery. DA receptor activation produced differential effects depending on the receptor subtype that was activated. D1 receptor family agonists generally enhanced cortical excitability and favored the emergence of epileptogenic activity. In contrast, D2 receptor family agonists had more variable effects on cortical excitability and the expression of epileptiform discharges. Activation of D1 or D2 receptors decreased the amplitude of non-NMDA-mediated excitatory postsynaptic potentials. In contrast, DA and D1 agonists increased the amplitude of NMDA-mediated potentials. Immunohistochemical analysis showed that the DA receptor subtypes and glutamate receptor subunits examined were present in all cortical layers and areas throughout development. Whole-cell voltage clamp recordings of pyramidal neurons visualized with differential interference contrast optics and infrared videomicroscopy indicated that these neurons displayed a persistent Na(+) current, followed by an outward current. DA reduced the outward current but had little effect on the persistent Na(+) current. These results suggest a dual role for DA's actions in the human cerebral cortex. Activation of D2 receptors or antagonism of D1 receptors may help control seizures in children.

Research paper thumbnail of Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons

eLife, Jan 8, 2015

Striatal dysfunction plays an important role in dystonia, but the striatal cell types that contri... more Striatal dysfunction plays an important role in dystonia, but the striatal cell types that contribute to abnormal movements are poorly defined. We demonstrate that conditional deletion of the DYT1 dystonia protein torsinA in embryonic progenitors of forebrain cholinergic and GABAergic neurons causes dystonic-like twisting movements that emerge during juvenile CNS maturation. The onset of these movements coincides with selective degeneration of dorsal striatal large cholinergic interneurons (LCI), and surviving LCI exhibit morphological, electrophysiological, and connectivity abnormalities. Consistent with the importance of this LCI pathology, murine dystonic-like movements are reduced significantly with an antimuscarinic agent used clinically, and we identify cholinergic abnormalities in postmortem striatal tissue from DYT1 dystonia patients. These findings demonstrate that dorsal LCI have a unique requirement for torsinA function during striatal maturation, and link abnormalities o...

Research paper thumbnail of Evidence from the R6/2 Mouse Model of Huntington's Disease for Using Abnormal Brain Metabolism as a Biomarker for Evaluating Therapeutic Approaches for Treatment

Future neurology

Huntington's disease (HD) is an autosomal dominant genetic disorder characterized by a progre... more Huntington's disease (HD) is an autosomal dominant genetic disorder characterized by a progression of motor abnormalities as well as cognitive and psychiatric symptoms [1]. Presently, there is no cure for HD and no treatment to reverse its course or prevent its onset. HD has been characterized primarily by significant degeneration of the striatum. In addition, imaging studies have shown alterations in extra-striatal regions including the cortex [2, 3], hippocampus, and hypothalamus [4]. Although previous functional magnetic resonance imaging (fMRI) studies in patients have yielded complex and heterogeneous findings, identifying functional alterations may serve as a useful tool for tracking the progression of HD and assessing the effects of therapeutic interventions. In a recent article Cepeda-Prado et el. use novel and groundbreaking fMRI methods to elucidate functional, structural, and metabolic alterations in the R6/2 mouse model of HD. Based on changes in relative cerebral br...

Research paper thumbnail of Pathological cell-cell interactions are necessary for striatal pathogenesis in a conditional mouse model of Huntington's disease

A critical issue in understanding Huntington's disease (HD) pathogenesis is how the ubiquitously ... more A critical issue in understanding Huntington's disease (HD) pathogenesis is how the ubiquitously expressed mutant huntingtin (mhtt) with an expanded polyglutamine repeat can cause selective toxicity of striatal and cortical neurons. Two potential cellular models may contribute to such specificity: expression of mhtt in these vulnerable neurons alone may be sufficient to result in their dysfunction and/or degeneration (cell-autonomous model); or mhtt in other cell types can elicit pathological cell-cell interactions to cause the vulnerable neurons to become dysfunctional and be at risk for degeneration (cell-cell interaction model). To distinguish between these two models, we have selectively expressed a neuropathogenic fragment of mhtt-exon1 in striatal medium spiny neurons (MSNs) by crossing a conditional mouse model of HD with a striatal-specific Cre mouse line. In this striatal model of HD, we observed progressive and cell-autonomous nuclear accumulation of mhtt aggregates in MSNs. Surprisingly, unlike the mouse model expressing mhtt-exon1 in all the neurons in the brain, the striatal model lacks significant locomotor deficits and striatal neuropathology including gliosis and dark degenerating neurons. Electrophysiological findings from acutely dissociated MSNs revealed a cell-autonomous deficit in N-methyl-d-aspartate (NMDA) receptor sensitivity to Mg 2+ , a deficit also present in other mouse models of HD. In conclusion, this study provides the first in vivo genetic evidence that pathological cell-cell interactions are necessary for striatal pathogenesis in a conditional mouse model of HD, and suggests a ''two-hit'' hypothesis in which both cell-autonomous toxicity and pathological cell-cell interactions are critical to HD pathogenesis.

Research paper thumbnail of Regional and cell-type-specific effects of DAMGO on striatal D1 and D2 dopamine receptor-expressing medium-sized spiny neurons

ASN NEURO, 2012

Cite this article as: Ma Y-Y, Cepeda C, Chatta P, Franklin L, Evans CJ and Levine MS (2012) Regio... more Cite this article as: Ma Y-Y, Cepeda C, Chatta P, Franklin L, Evans CJ and Levine MS (2012) Regional and cell-type-specific effects of DAMGO on striatal D1 and D2 dopamine receptor-expressing medium-sized spiny neurons. ASN NEURO 4(2):art:e00077.

Research paper thumbnail of Altered Excitatory and Inhibitory Inputs to Striatal Medium-Sized Spiny Neurons and Cortical Pyramidal Neurons in the Q175 Mouse Model of Huntington's Disease

Journal of neurophysiology, Jan 11, 2015

The Q175 knock-in mouse model of Huntington's disease (HD) carries a CAG trinucleotide expans... more The Q175 knock-in mouse model of Huntington's disease (HD) carries a CAG trinucleotide expansion of the human mutant huntingtin allele in its native mouse genomic context and recapitulates the genotype more closely than transgenic models. In this study we examined the progression of changes in intrinsic membrane properties and excitatory and inhibitory synaptic transmission using whole-cell patch clamp recordings of medium-sized spiny neurons (MSNs) in the dorsolateral striatum and cortical pyramidal neurons (CPNs) in layers 2/3 of the primary motor cortex in brain slices from heterozygous (Q175(+/-)) and homozygous (Q175(+/+)) mice. Input resistance in MSNs from Q175(+/+) and Q175(+/-) mice was significantly increased compared to wildtype (WT) littermates beginning at 2 months. Furthermore, the frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) was significantly reduced in MSNs from Q175(+/+) and Q175(+/-) mice compared to WTs beginning at 7 months....

Research paper thumbnail of Functional Differences Between Direct and Indirect Striatal Output Pathways in Huntington's Disease

Journal of Huntington's disease, 2012

There is morphological evidence for differential alterations in striatal medium-sized spiny neuro... more There is morphological evidence for differential alterations in striatal medium-sized spiny neurons (MSNs) giving rise to the direct and indirect output pathways in Huntington's disease (HD). MSNs of the indirect pathway appear to be particularly vulnerable and markers for these neurons are lost early in postmortem brains and in genetic mouse models. In contrast, MSNs of the direct pathway appear to be relatively spared in the early stages. Because of the great morphological and electrophysiological similarities between MSNs of these pathways, until recently it was difficult to tease apart their functional alterations in HD models. The recent use of the enhanced green fluorescent protein gene as a reporter to identify dopamine D1 (direct pathway) and D2 (indirect pathway) receptor-expressing MSNs has made it possible to examine synaptic function in each pathway. The outcomes of such studies demonstrate significant time-dependent changes in the balance of excitatory and inhibitor...

Research paper thumbnail of Targeted expression of μ-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward

Nature neuroscience, 2014

μ-opioid receptors (MORs) are necessary for the analgesic and addictive effects of opioids such a... more μ-opioid receptors (MORs) are necessary for the analgesic and addictive effects of opioids such as morphine, but the MOR-expressing neuronal populations that mediate the distinct opiate effects remain elusive. Here we devised a new conditional bacterial artificial chromosome rescue strategy to show, in mice, that targeted MOR expression in a subpopulation of striatal direct-pathway neurons enriched in the striosome and nucleus accumbens, in an otherwise MOR-null background, restores opiate reward and opiate-induced striatal dopamine release and partially restores motivation to self administer an opiate. However, these mice lack opiate analgesia or withdrawal. We used Cre-mediated deletion of the rescued MOR transgene to establish that expression of the MOR transgene in the striatum, rather than in extrastriatal sites, is needed for the restoration of opiate reward. Our study demonstrates that a subpopulation of striatal direct-pathway neurons is sufficient to support opiate reward-d...

Research paper thumbnail of In Rasmussen Encephalitis, Hemichannels Associated with Microglial Activation are linked to Cortical Pyramidal Neuron Coupling: A Possible Mechanism for Cellular Hyperexcitability

CNS neuroscience & therapeutics, 2015

Rasmussen encephalitis (RE) is a rare but devastating condition, mainly in children, characterize... more Rasmussen encephalitis (RE) is a rare but devastating condition, mainly in children, characterized by sustained brain inflammation, atrophy of one cerebral hemisphere, epilepsy, and progressive cognitive deterioration. The etiology of RE-induced seizures associated with the inflammatory process remains unknown. Cortical tissue samples from children undergoing surgical resections for the treatment of RE (n = 16) and non-RE (n = 12) were compared using electrophysiological, morphological, and immunohistochemical techniques to examine neuronal properties and the relationship with microglial activation using the specific microglia/macrophage calcium-binding protein, IBA1 in conjunction with connexins and pannexin expression. Compared with non-RE cases, pyramidal neurons from RE cases displayed increased cell capacitance and reduced input resistance. However, neuronal somatic areas were not increased in size. Instead, intracellular injection of biocytin led to increased dye coupling betw...

Research paper thumbnail of Differential Synaptic and Extrasynaptic Glutamate-Receptor Alterations in Striatal Medium-Sized Spiny Neurons of Aged YAC128 Huntington’s Disease Mice

PLoS Currents, 2014

Huntington&am... more Huntington's disease (HD) is a late-onset, slowly progressing neurodegenerative disorder caused by an expansion of glutamine repeats. The YAC128 mouse model has been widely used to study the progression of HD symptoms, but little is known about synaptic alterations in very old animals. The present experiments examined synaptic properties of striatal medium-sized spiny neurons (MSNs) in 16 month-old YAC128 mice. These mice were crossed with mice expressing enhanced green fluorescent protein (EGFP) under the control of either D1 or D2 dopamine receptor promoters to identify MSNs originating the direct and indirect pathways, respectively. The input-output curves of evoked excitatory postsynaptic currents mediated by activation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or N-methyl-D-aspartate (NMDA) receptors were reduced in MSNs in both pathways. In the presence of DL-threo-β-Benzyloxyaspartic acid (DL-TBOA), a glutamate transporter blocker used to increase activation of extrasynaptic receptors, NMDA receptor-mediated currents displayed altered amplitudes, longer decay times, and greater charge (response areas) in both direct and indirect pathway MSNs in YAC128 mice compared to wildtype controls. Amplitudes were significantly increased, primarily in direct pathway MSNs while normalized areas were significantly increased only in indirect pathway MSNs, suggesting that the two types of MSNs are affected in different ways. It may be that indirect pathway neurons are more susceptible to changes in glutamate transport. Taken together, the present findings demonstrate differential alterations in synaptic versus extrasynaptic NMDA receptors in both direct and indirect pathway MSNs in late HD, which may contribute to the dysfunction and degeneration in both pathways.

Research paper thumbnail of Transient and progressive electrophysiological alterations in the corticostriatal pathway in a mouse model of Huntington's disease

The Journal of neuroscience : the official journal of the Society for Neuroscience, 2003

Alterations in the corticostriatal pathway may precede symptomatology and striatal cell death in ... more Alterations in the corticostriatal pathway may precede symptomatology and striatal cell death in Huntington's disease (HD) patients. Here we examined spontaneous EPSCs in striatal medium-sized spiny neurons in slices from a mouse model of HD (R6/2). Spontaneous EPSC frequency was similar in young (3-4 weeks) transgenics and controls but decreased significantly in transgenics when overt behavioral symptoms began (5-7 weeks) and was most pronounced in severely impaired transgenics (11-15 weeks). These differences were maintained after bicuculline or tetrodotoxin, indicating they were specific to glutamatergic input and likely presynaptic in origin. Decreases in presynaptic and postsynaptic protein markers, synaptophysin and postsynaptic density-95, occurred in 11-15 week R6/2 mice, supporting the electrophysiological results. Furthermore, isolated, large-amplitude synaptic events (>100 pA) occurred more frequently in transgenic animals, particularly at 5-7 weeks, suggesting add...

Research paper thumbnail of The role of dopamine in huntington's disease

Progress in Brain Research, 2014

Research paper thumbnail of Drug-primed reinstatement of cocaine seeking in mice: increased excitability of medium-sized spiny neurons in the nucleus accumbens

ASN NEURO, 2013

Drug-primed reinstatement of cocaine seeking in mice: increased excitability of medium-sized spin... more Drug-primed reinstatement of cocaine seeking in mice: increased excitability of medium-sized spiny neurons in the nucleus accumbens. ASN NEURO 5(4):art:e00122.

Research paper thumbnail of Increased GABAergic function in mouse models of Huntington's disease: Reversal by BDNF

Journal of Neuroscience Research, 2004

Huntington&am... more Huntington's disease (HD) is characterized by loss of striatal gamma-aminobutyric acid (GABA)ergic medium-sized spiny projection neurons (MSSNs), whereas some classes of striatal interneurons are relatively spared. Striatal interneurons provide most of the inhibitory synaptic input to MSSNs and use GABA as their neurotransmitter. We reported previously alterations in glutamatergic synaptic activity in the R6/2 and R6/1 mouse models of HD. In the present study, we used whole-cell voltage clamp recordings to examine GABAergic synaptic currents in MSSNs from striatal slices in these two mouse models compared to those in age-matched control littermates. The frequency of spontaneous GABAergic synaptic currents was increased significantly in MSSNs from R6/2 transgenics starting around 5-7 weeks (when the overt behavioral phenotype begins) and continuing in 9-14-week-old mice. A similar increase was observed in 12-15-month-old R6/1 transgenics. Bath application of brain-derived neurotrophic factor, which is downregulated in HD, significantly reduced the frequency of spontaneous GABAergic synaptic currents in MSSNs from R6/2 but not control mice at 9-14 weeks. Increased GABA current densities also occurred in acutely isolated MSSNs from R6/2 animals. Immunofluorescence demonstrated increased expression of the ubiquitous alpha1 subunit of GABA(A) receptors in MSSNs from R6/2 animals. These results indicate that increases in spontaneous GABAergic synaptic currents and postsynaptic receptor function occur in parallel to progressive decreases in glutamatergic inputs to MSSNs. In conjunction, both changes will severely alter striatal outputs to target areas involved in the control of movement.

Research paper thumbnail of Pacemaker GABA synaptic activity may contribute to network synchronization in pediatric cortical dysplasia

Spontaneous pacemaker γ-aminobutyric acid (GABA) receptor-mediated synaptic activity (PGA) occurs... more Spontaneous pacemaker γ-aminobutyric acid (GABA) receptor-mediated synaptic activity (PGA) occurs in a subset of tissue samples from pediatric epilepsy surgery patients. In the present study, based on single-cell electrophysiological recordings from 120 cases, we describe the etiologies, cell types, and primary electrophysiological features of PGA. Cells displaying PGA occurred more frequently in the areas of greatest anatomical abnormality in cases of focal cortical dysplasia (CD), often associated with hemimegalencephaly (HME), and only rarely in non-CD etiologies. PGA was characterized by rhythmic synaptic events (5-10Hz) and was observed in normal-like, dysmorphic cytomegalic, and immature pyramidal neurons. PGA was action potential-dependent, mediated by GABAA receptors, and unaffected by antagonism of glutamate receptors. We propose that PGA is a unique electrophysiological characteristic associated with CD and HME. It could represent an abnormal signal that may contribute to epileptogenesis in malformed postnatal cortex by facilitating pyramidal neuron synchrony.

Research paper thumbnail of Neurons Recorded from Pediatric Epilepsy Surgery Patients with Cortical Dysplasia

Epilepsia, 2000

Purpose: Cortical dysplasia (CD) is a common pathological substrate in patients with early-onset ... more Purpose: Cortical dysplasia (CD) is a common pathological substrate in patients with early-onset childhood epilepsy. In CD tissue, little is known about the mechanisms responsible for cellular hyperexcitability. In this study, we report initial electrophysiological and morphological observations from normal and dysmorphic cells in pediatric CD patients.

Research paper thumbnail of NMDA Receptor Alterations in Neurons from Pediatric Cortical Dysplasia Tissue

Cerebral Cortex, 2004

The subunit composition of glutamate receptors affects their functional properties, and could con... more The subunit composition of glutamate receptors affects their functional properties, and could contribute to abnormal electrophysiology in pediatric cortical dysplasia (CD). We examined electrophysiological responses and subunit assembly of N-methyl-D-aspartate (NMDA) receptors in acutely dissociated normal-appearing pyramidal and cytomegalic neurons from CD tissue and normal-appearing pyramidal neurons from non-CD tissue. In most cytomegalic and ∼30% of normal-appearing pyramidal neurons from CD tissue, NMDA currents showed decreased Mg 2+ sensitivity compared with neurons from non-CD tissue. Ifenprodil had less effect in CD compared with non-CD neurons, indicating a functional loss of NR2B subunits. NMDA-evoked current density was decreased in cytomegalic compared with normal-appearing neurons. Single-cell reverse transcriptase polymerase chain reaction showed that all non-CD neurons expressed NR2B subunit mRNA. By comparison, 22% of pyramidal neurons in CD tissue lacked NR2B mRNA. Immunofluorescence showed a decrease in NR2B subunit expression in cytomegalic neurons and a subset of normal-appearing pyramidal neurons from CD tissue. Taken together, these results demonstrate the presence of NMDA receptors with altered subunit composition and Mg 2+ sensitivity that could contribute to functional abnormalities in CD.

Research paper thumbnail of Pediatric Cortical Dysplasia: Correlations between Neuroimaging, Electrophysiology and Location of Cytomegalic Neurons and Balloon Cells and Glutamate/GABA Synaptic Circuits

Developmental Neuroscience, 2005

Seizures in cortical dysplasia (CD) could be from cytomegalic neurons and balloon cells acting as... more Seizures in cortical dysplasia (CD) could be from cytomegalic neurons and balloon cells acting as epileptic 'pacemakers', or abnormal neurotransmission. This study examined these hypotheses using in vitro electrophysiological techniques to determine intrinsic membrane properties and spontaneous glutamatergic and GABAergic synaptic activity for normal-pyramidal neurons, cytomegalic neurons and balloon cells from 67 neocortical sites originating from 43 CD patients (ages 0.2-14 years). Magnetic resonance imaging (MRI), 18 fluoro-2-deoxyglucose positron emission tomography (FDG-PET) and electrocorticography graded cortical sample sites from least to worst CD abnormality. Results found that cytomegalic neurons and balloon cells were observed more frequently in areas of severe CD compared with mild or normal CD regions as assessed by FDG-PET/MRI. Cytomegalic neurons (but not balloon cells) correlated with the worst electrocorticography scores. Electrophysiological recordings demonstrated that cytomegalic and normalpyramidal neurons displayed similar firing properties without intrinsic bursting. By contrast, balloon cells were electrically silent. Normal-pyramidal and cytomegalic neurons displayed decreased spontaneous glutamatergic synaptic activity in areas of severe FDG-PET/MRI abnormalities compared with normal regions, while GABAergic activity was unaltered. In CD, these findings indicate that cytomegalic neurons (but not balloon cells) might contribute to epileptogenesis, but are not likely to be 'pacemaker' cells capable of spontaneous paroxysmal depolarizations. Furthermore, there was more GABA relative to glutamate synaptic neurotransmission in areas of severe CD. Thus, in CD tissue alternate mechanisms of epileptogenesis should be considered, and we suggest that GABAergic synaptic circuits interacting with cytomegalic and normal-pyramidal neurons with immature receptor properties might contribute to seizure generation.

Research paper thumbnail of Human Cortical Dysplasia and Epilepsy: An Ontogenetic Hypothesis Based on Volumetric MRI and NeuN Neuronal Density and Size Measurements

Cerebral Cortex, 2004

In epilepsy patients with cortical dysplasia (CD), this study determined the probable ontogenetic... more In epilepsy patients with cortical dysplasia (CD), this study determined the probable ontogenetic timing of pathogenesis based on the number, location and appearance of neurons. Magnetic resonance imaging (MRI) determined gray and white matter volumes of affected and nonaffected cerebral hemispheres, and gray and white matter neuronalnuclear protein (NeuN) densities and sizes were assessed in epilepsy surgery patients (0.2--38 years) with CD (n 5 25) and non-CD etiologies (n 5 14), and compared with autopsy cases (n 5 13; 0--33 years). Pathology group, seizure type and age at surgery were compared against MRI and NeuN data. CD patients demonstrated increased MRI cerebral (3%) and gray matter (8%) volumes of the affected compared with non-affected cerebral hemisphere, and increased layer 1 (131%), upper cortical (9--23%) and white matter (28--77%) NeuN densities compared with autopsy cases. Non-CD cases showed decreased cerebral volumes of the affected hemisphere (14--18%) without changes in NeuN densities. Compared with autopsy cases, in CD and non-CD patients, cortical neurons were hypertrophied. Patients with a history of infantile spasms had a 40% increase in the size of layer 1 neurons compared with cases without spasms. By age, regardless of pathology group, there were logarithmic increases in MRI cerebral and white matter volumes, logarithmic increases in the size of lower gray and superficial white matter neurons, and logarithmic decreases in gray and white matter neuronal densities. These results support the concept that there were more neurons than expected in layer 1, gray, and white matter of CD patients compared with non-CD and autopsy cases. In addition, the location and appearance of neurons are consistent with the hypothesis that CD is the consequence of abnormalities occurring late in corticoneurogenesis that involve excessive neurogenesis with retention of pre-plate cells in the molecular layer and subplate regions.

Research paper thumbnail of Dopamine Enhancement of NMDA Currents in Dissociated Medium-Sized Striatal Neurons: Role of D1 Receptors and DARPP-32

Dopamine (DA), via activation of D1 receptors, enhances N -methyl- D -aspartate (NMDA)-evoked res... more Dopamine (DA), via activation of D1
receptors, enhances
N
-methyl-
D
-aspartate (NMDA)-evoked responses
in striatal neurons. The present investigation examined further the
properties of this enhancement and the potential mechanisms by
which this enhancement might be effected. Dissociated medium-sized
striatal neurons were obtained from intact rats and mice or mutant
mice lacking the DA and cyclic adenosine 3
,5
monophosphate
(cAMP)-regulated phosphoprotein of
M
R
32,000 (DARPP-32).
NMDA (10 –1,000
M) induced inward currents in all neurons. In
acutely dissociated neurons from intact rats or mice, activation of D1
receptors with the selective agonist, SKF 81297, produced a dose-
dependent enhancement of NMDA currents. This enhancement was
reduced by the selective D1 receptor antagonist SKF 83566. Quinpi-
role, a D2 receptor agonist alone, produced small reductions of
NMDA currents. However, it consistently and significantly reduced
the enhancement of NMDA currents by D1 agonists. In dissociated
striatal neurons, in conditions that minimized the contributions of
voltage-gated Ca
2
conductances, the D1-induced potentiation was
not altered by blockade of L-type voltage-gated Ca
2
conductances in
contrast to results in slices. The DARPP-32 signaling pathway has an
important role in D1 modulation of NMDA currents. In mice lacking
DARPP-32, the enhancement was significantly reduced. Furthermore,
okadaic acid, a protein phosphatase 1 (PP-1) inhibitor, increased
D1-induced potentiation, suggesting that constitutively active PP-1
attenuates D1-induced potentiation. Finally, activation of D1 recep-
tors produced differential effects on NMDA and gamma aminobutyric
acid (GABA)-induced currents in the same cells, enhancing NMDA
currents and inhibiting GABA currents. Thus simultaneous activation
of D1, NMDA, and GABA receptors could predispose medium-sized
spiny neurons toward excitation. Taken together, the present findings
indicate that the unique potentiation of NMDA receptor function by
activation of the D1 receptor signaling cascade can be controlled by
multiple mechanisms and has major influences on neuronal function

Research paper thumbnail of Electrophysiological and Morphological Analyses of Cortical Neurons Obtained from Children with Catastrophic Epilepsy: Dopamine Receptor Modulation of Glutamatergic Responses

Developmental Neuroscience, 1999

The present study examined the electrophysiological effects produced by activation of specific do... more The present study examined the electrophysiological effects produced by activation of specific dopamine (DA) receptors and the distribution of DA receptor subtypes and glutamate receptor subunits [N-methyl-D-aspartate (NMDAR1) and GluR1] in cortical tissue samples obtained from children (ages 3 months to 16 years) undergoing epilepsy surgery. DA receptor activation produced differential effects depending on the receptor subtype that was activated. D1 receptor family agonists generally enhanced cortical excitability and favored the emergence of epileptogenic activity. In contrast, D2 receptor family agonists had more variable effects on cortical excitability and the expression of epileptiform discharges. Activation of D1 or D2 receptors decreased the amplitude of non-NMDA-mediated excitatory postsynaptic potentials. In contrast, DA and D1 agonists increased the amplitude of NMDA-mediated potentials. Immunohistochemical analysis showed that the DA receptor subtypes and glutamate receptor subunits examined were present in all cortical layers and areas throughout development. Whole-cell voltage clamp recordings of pyramidal neurons visualized with differential interference contrast optics and infrared videomicroscopy indicated that these neurons displayed a persistent Na(+) current, followed by an outward current. DA reduced the outward current but had little effect on the persistent Na(+) current. These results suggest a dual role for DA's actions in the human cerebral cortex. Activation of D2 receptors or antagonism of D1 receptors may help control seizures in children.

Research paper thumbnail of Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons

eLife, Jan 8, 2015

Striatal dysfunction plays an important role in dystonia, but the striatal cell types that contri... more Striatal dysfunction plays an important role in dystonia, but the striatal cell types that contribute to abnormal movements are poorly defined. We demonstrate that conditional deletion of the DYT1 dystonia protein torsinA in embryonic progenitors of forebrain cholinergic and GABAergic neurons causes dystonic-like twisting movements that emerge during juvenile CNS maturation. The onset of these movements coincides with selective degeneration of dorsal striatal large cholinergic interneurons (LCI), and surviving LCI exhibit morphological, electrophysiological, and connectivity abnormalities. Consistent with the importance of this LCI pathology, murine dystonic-like movements are reduced significantly with an antimuscarinic agent used clinically, and we identify cholinergic abnormalities in postmortem striatal tissue from DYT1 dystonia patients. These findings demonstrate that dorsal LCI have a unique requirement for torsinA function during striatal maturation, and link abnormalities o...

Research paper thumbnail of Evidence from the R6/2 Mouse Model of Huntington's Disease for Using Abnormal Brain Metabolism as a Biomarker for Evaluating Therapeutic Approaches for Treatment

Future neurology

Huntington's disease (HD) is an autosomal dominant genetic disorder characterized by a progre... more Huntington's disease (HD) is an autosomal dominant genetic disorder characterized by a progression of motor abnormalities as well as cognitive and psychiatric symptoms [1]. Presently, there is no cure for HD and no treatment to reverse its course or prevent its onset. HD has been characterized primarily by significant degeneration of the striatum. In addition, imaging studies have shown alterations in extra-striatal regions including the cortex [2, 3], hippocampus, and hypothalamus [4]. Although previous functional magnetic resonance imaging (fMRI) studies in patients have yielded complex and heterogeneous findings, identifying functional alterations may serve as a useful tool for tracking the progression of HD and assessing the effects of therapeutic interventions. In a recent article Cepeda-Prado et el. use novel and groundbreaking fMRI methods to elucidate functional, structural, and metabolic alterations in the R6/2 mouse model of HD. Based on changes in relative cerebral br...

Research paper thumbnail of Pathological cell-cell interactions are necessary for striatal pathogenesis in a conditional mouse model of Huntington's disease

A critical issue in understanding Huntington's disease (HD) pathogenesis is how the ubiquitously ... more A critical issue in understanding Huntington's disease (HD) pathogenesis is how the ubiquitously expressed mutant huntingtin (mhtt) with an expanded polyglutamine repeat can cause selective toxicity of striatal and cortical neurons. Two potential cellular models may contribute to such specificity: expression of mhtt in these vulnerable neurons alone may be sufficient to result in their dysfunction and/or degeneration (cell-autonomous model); or mhtt in other cell types can elicit pathological cell-cell interactions to cause the vulnerable neurons to become dysfunctional and be at risk for degeneration (cell-cell interaction model). To distinguish between these two models, we have selectively expressed a neuropathogenic fragment of mhtt-exon1 in striatal medium spiny neurons (MSNs) by crossing a conditional mouse model of HD with a striatal-specific Cre mouse line. In this striatal model of HD, we observed progressive and cell-autonomous nuclear accumulation of mhtt aggregates in MSNs. Surprisingly, unlike the mouse model expressing mhtt-exon1 in all the neurons in the brain, the striatal model lacks significant locomotor deficits and striatal neuropathology including gliosis and dark degenerating neurons. Electrophysiological findings from acutely dissociated MSNs revealed a cell-autonomous deficit in N-methyl-d-aspartate (NMDA) receptor sensitivity to Mg 2+ , a deficit also present in other mouse models of HD. In conclusion, this study provides the first in vivo genetic evidence that pathological cell-cell interactions are necessary for striatal pathogenesis in a conditional mouse model of HD, and suggests a ''two-hit'' hypothesis in which both cell-autonomous toxicity and pathological cell-cell interactions are critical to HD pathogenesis.

Research paper thumbnail of Regional and cell-type-specific effects of DAMGO on striatal D1 and D2 dopamine receptor-expressing medium-sized spiny neurons

ASN NEURO, 2012

Cite this article as: Ma Y-Y, Cepeda C, Chatta P, Franklin L, Evans CJ and Levine MS (2012) Regio... more Cite this article as: Ma Y-Y, Cepeda C, Chatta P, Franklin L, Evans CJ and Levine MS (2012) Regional and cell-type-specific effects of DAMGO on striatal D1 and D2 dopamine receptor-expressing medium-sized spiny neurons. ASN NEURO 4(2):art:e00077.

Research paper thumbnail of Altered Excitatory and Inhibitory Inputs to Striatal Medium-Sized Spiny Neurons and Cortical Pyramidal Neurons in the Q175 Mouse Model of Huntington's Disease

Journal of neurophysiology, Jan 11, 2015

The Q175 knock-in mouse model of Huntington's disease (HD) carries a CAG trinucleotide expans... more The Q175 knock-in mouse model of Huntington's disease (HD) carries a CAG trinucleotide expansion of the human mutant huntingtin allele in its native mouse genomic context and recapitulates the genotype more closely than transgenic models. In this study we examined the progression of changes in intrinsic membrane properties and excitatory and inhibitory synaptic transmission using whole-cell patch clamp recordings of medium-sized spiny neurons (MSNs) in the dorsolateral striatum and cortical pyramidal neurons (CPNs) in layers 2/3 of the primary motor cortex in brain slices from heterozygous (Q175(+/-)) and homozygous (Q175(+/+)) mice. Input resistance in MSNs from Q175(+/+) and Q175(+/-) mice was significantly increased compared to wildtype (WT) littermates beginning at 2 months. Furthermore, the frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) was significantly reduced in MSNs from Q175(+/+) and Q175(+/-) mice compared to WTs beginning at 7 months....

Research paper thumbnail of Functional Differences Between Direct and Indirect Striatal Output Pathways in Huntington's Disease

Journal of Huntington's disease, 2012

There is morphological evidence for differential alterations in striatal medium-sized spiny neuro... more There is morphological evidence for differential alterations in striatal medium-sized spiny neurons (MSNs) giving rise to the direct and indirect output pathways in Huntington's disease (HD). MSNs of the indirect pathway appear to be particularly vulnerable and markers for these neurons are lost early in postmortem brains and in genetic mouse models. In contrast, MSNs of the direct pathway appear to be relatively spared in the early stages. Because of the great morphological and electrophysiological similarities between MSNs of these pathways, until recently it was difficult to tease apart their functional alterations in HD models. The recent use of the enhanced green fluorescent protein gene as a reporter to identify dopamine D1 (direct pathway) and D2 (indirect pathway) receptor-expressing MSNs has made it possible to examine synaptic function in each pathway. The outcomes of such studies demonstrate significant time-dependent changes in the balance of excitatory and inhibitor...

Research paper thumbnail of Targeted expression of μ-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward

Nature neuroscience, 2014

μ-opioid receptors (MORs) are necessary for the analgesic and addictive effects of opioids such a... more μ-opioid receptors (MORs) are necessary for the analgesic and addictive effects of opioids such as morphine, but the MOR-expressing neuronal populations that mediate the distinct opiate effects remain elusive. Here we devised a new conditional bacterial artificial chromosome rescue strategy to show, in mice, that targeted MOR expression in a subpopulation of striatal direct-pathway neurons enriched in the striosome and nucleus accumbens, in an otherwise MOR-null background, restores opiate reward and opiate-induced striatal dopamine release and partially restores motivation to self administer an opiate. However, these mice lack opiate analgesia or withdrawal. We used Cre-mediated deletion of the rescued MOR transgene to establish that expression of the MOR transgene in the striatum, rather than in extrastriatal sites, is needed for the restoration of opiate reward. Our study demonstrates that a subpopulation of striatal direct-pathway neurons is sufficient to support opiate reward-d...

Research paper thumbnail of In Rasmussen Encephalitis, Hemichannels Associated with Microglial Activation are linked to Cortical Pyramidal Neuron Coupling: A Possible Mechanism for Cellular Hyperexcitability

CNS neuroscience & therapeutics, 2015

Rasmussen encephalitis (RE) is a rare but devastating condition, mainly in children, characterize... more Rasmussen encephalitis (RE) is a rare but devastating condition, mainly in children, characterized by sustained brain inflammation, atrophy of one cerebral hemisphere, epilepsy, and progressive cognitive deterioration. The etiology of RE-induced seizures associated with the inflammatory process remains unknown. Cortical tissue samples from children undergoing surgical resections for the treatment of RE (n = 16) and non-RE (n = 12) were compared using electrophysiological, morphological, and immunohistochemical techniques to examine neuronal properties and the relationship with microglial activation using the specific microglia/macrophage calcium-binding protein, IBA1 in conjunction with connexins and pannexin expression. Compared with non-RE cases, pyramidal neurons from RE cases displayed increased cell capacitance and reduced input resistance. However, neuronal somatic areas were not increased in size. Instead, intracellular injection of biocytin led to increased dye coupling betw...

Research paper thumbnail of Differential Synaptic and Extrasynaptic Glutamate-Receptor Alterations in Striatal Medium-Sized Spiny Neurons of Aged YAC128 Huntington’s Disease Mice

PLoS Currents, 2014

Huntington&am... more Huntington's disease (HD) is a late-onset, slowly progressing neurodegenerative disorder caused by an expansion of glutamine repeats. The YAC128 mouse model has been widely used to study the progression of HD symptoms, but little is known about synaptic alterations in very old animals. The present experiments examined synaptic properties of striatal medium-sized spiny neurons (MSNs) in 16 month-old YAC128 mice. These mice were crossed with mice expressing enhanced green fluorescent protein (EGFP) under the control of either D1 or D2 dopamine receptor promoters to identify MSNs originating the direct and indirect pathways, respectively. The input-output curves of evoked excitatory postsynaptic currents mediated by activation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or N-methyl-D-aspartate (NMDA) receptors were reduced in MSNs in both pathways. In the presence of DL-threo-β-Benzyloxyaspartic acid (DL-TBOA), a glutamate transporter blocker used to increase activation of extrasynaptic receptors, NMDA receptor-mediated currents displayed altered amplitudes, longer decay times, and greater charge (response areas) in both direct and indirect pathway MSNs in YAC128 mice compared to wildtype controls. Amplitudes were significantly increased, primarily in direct pathway MSNs while normalized areas were significantly increased only in indirect pathway MSNs, suggesting that the two types of MSNs are affected in different ways. It may be that indirect pathway neurons are more susceptible to changes in glutamate transport. Taken together, the present findings demonstrate differential alterations in synaptic versus extrasynaptic NMDA receptors in both direct and indirect pathway MSNs in late HD, which may contribute to the dysfunction and degeneration in both pathways.

Research paper thumbnail of Transient and progressive electrophysiological alterations in the corticostriatal pathway in a mouse model of Huntington's disease

The Journal of neuroscience : the official journal of the Society for Neuroscience, 2003

Alterations in the corticostriatal pathway may precede symptomatology and striatal cell death in ... more Alterations in the corticostriatal pathway may precede symptomatology and striatal cell death in Huntington's disease (HD) patients. Here we examined spontaneous EPSCs in striatal medium-sized spiny neurons in slices from a mouse model of HD (R6/2). Spontaneous EPSC frequency was similar in young (3-4 weeks) transgenics and controls but decreased significantly in transgenics when overt behavioral symptoms began (5-7 weeks) and was most pronounced in severely impaired transgenics (11-15 weeks). These differences were maintained after bicuculline or tetrodotoxin, indicating they were specific to glutamatergic input and likely presynaptic in origin. Decreases in presynaptic and postsynaptic protein markers, synaptophysin and postsynaptic density-95, occurred in 11-15 week R6/2 mice, supporting the electrophysiological results. Furthermore, isolated, large-amplitude synaptic events (>100 pA) occurred more frequently in transgenic animals, particularly at 5-7 weeks, suggesting add...

Research paper thumbnail of The role of dopamine in huntington's disease

Progress in Brain Research, 2014

Research paper thumbnail of Drug-primed reinstatement of cocaine seeking in mice: increased excitability of medium-sized spiny neurons in the nucleus accumbens

ASN NEURO, 2013

Drug-primed reinstatement of cocaine seeking in mice: increased excitability of medium-sized spin... more Drug-primed reinstatement of cocaine seeking in mice: increased excitability of medium-sized spiny neurons in the nucleus accumbens. ASN NEURO 5(4):art:e00122.