Matthew During - Academia.edu (original) (raw)

Papers by Matthew During

Neuron, Jan 30, 2009

The precise subunit composition of synaptic ionotropic receptors in the brain is poorly understoo... more The precise subunit composition of synaptic ionotropic receptors in the brain is poorly understood. This information is of particular importance with regard to AMPA-type glutamate receptors, the multimeric complexes assembled from GluA1-A4 subunits, as the trafficking of these receptors into and out of synapses is proposed to depend upon the subunit composition of the receptor. We report a molecular quantification of synaptic AMPA receptors (AMPARs) by employing a single-cell genetic approach coupled with electrophysiology in hippocampal CA1 pyramidal neurons. In contrast to prevailing views, we find that GluA1A2 heteromers are the dominant AMPARs at CA1 cell synapses (approximately 80%). In cells lacking GluA1, -A2, and -A3, synapses are devoid of AMPARs, yet synaptic NMDA receptors (NMDARs) and dendritic morphology remain unchanged. These data demonstrate a functional dissociation of AMPARs from trafficking of NMDARs and neuronal morphogenesis. This study provides a functional qua...

Journal of …, 2005

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Frontiers in Behavioral Neuroscience

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and autism.... more Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and autism. FXS is also accompanied by attention problems, hyperactivity, anxiety, aggression, poor sleep, repetitive behaviors, and self-injury. Recent work supports the role of γ-aminobutyric-acid (GABA), the primary inhibitory neurotransmitter in the brain, in mediating symptoms of FXS. Deficits in GABA machinery have been observed in a mouse model of FXS, including a loss of tonic inhibition in the amygdala, which is mediated by extrasynaptic GABA A receptors. Humans with FXS also show reduced GABA A receptor availability. Here, we sought to evaluate the potential of gaboxadol (also called OV101 and THIP), a selective and potent agonist for delta-subunit-containing extrasynaptic GABA A receptors (dSEGA), as a therapeutic agent for FXS by assessing its ability to normalize aberrant behaviors in a relatively uncharacterized mouse model of FXS (Fmr1 KO2 mice). Four behavioral domains (hyperactivity, anxiety, aggression, and repetitive behaviors) were probed using a battery of behavioral assays. The results showed that Fmr1 KO2 mice were hyperactive, had abnormal anxiety-like behavior, were more irritable and aggressive, and had an increased frequency of repetitive behaviors compared to wild-type (WT) littermates, which are all behavioral deficits reminiscent of individuals with FXS. Treatment with gaboxadol normalized all of the aberrant behaviors observed in Fmr1 KO2 mice back to WT levels, providing evidence of its potential benefit for treating FXS. We show that the potentiation of extrasynaptic GABA receptors alone, by gaboxadol, is sufficient to normalize numerous behavioral deficits in the FXS model using endpoints that are directly translatable to the clinical presentation of FXS. Taken together, these data support the future evaluation of gaboxadol in individuals with FXS, particularly with regard to symptoms of hyperactivity, anxiety, irritability, aggression, and repetitive behaviors.

Platelets, Jan 21, 2017

GluN1 is a mandatory component of N-methyl-D-aspartate receptors (NMDARs) best known for their ro... more GluN1 is a mandatory component of N-methyl-D-aspartate receptors (NMDARs) best known for their roles in the brain, but with increasing evidence for relevance in peripheral tissues, including platelets. Certain anti-GluN1 antibodies reduce brain infarcts in rodent models of ischaemic stroke. There is also evidence that human anti-GluN1 autoantibodies reduce neuronal damage in stroke patients, but the underlying mechanism is unclear. This study investigated whether anti-GluN1-mediated neuroprotection involves inhibition of platelet function. Four commercial anti-GluN1 antibodies were screened for their abilities to inhibit human platelet aggregation. Haematological parameters were examined in rats vaccinated with GluN1. Platelet effects of a mouse monoclonal antibody targeting the glycine-binding region of GluN1 (GluN1-S2) were tested in assays of platelet activation, aggregation and thrombus formation. The epitope of anti-GluN1-S2 was mapped and the mechanism of antibody action model...

Medical Intelligence Unit, 2006

This volume is unique to the existing literature in the Peptide Nucleic Acid field, in that it fo... more This volume is unique to the existing literature in the Peptide Nucleic Acid field, in that it focuses on comparing and contrasting PNA with other available oligonucleotide homologues and considers areas in which these biomolecules could be profitably applied to clinical and diagnostic applications. Part I of the book addresses comparative strengths and weaknesses of various nucleoside homologues. Part II of the book addresses specific translational or clinical applications for PNA and related antisense biomolecules. The ...

The present invention involves the delivery of cells of myeloid origin to a mammalian nervous sys... more The present invention involves the delivery of cells of myeloid origin to a mammalian nervous system and to the use of such cells for treatment of disorders of glial pathology, disorders of neuronal loss or dysfunction, or other disorders, diseases, or trauma involving the nervous system. The invention also includes the delivery of such cells that are transfected with foreign nucleic acid for delivery of potential gene therapy products directly into the CNS.

Journal of Liquid Chromatography, 1994

Abstract Intracerebral microdialysis has become a standard method for neurochemistry studies and ... more Abstract Intracerebral microdialysis has become a standard method for neurochemistry studies and is becoming recognized as an important new method for pharmacological studies. The technique permits repeated measurement of drug concentrations in the brain extracellular fluid with minimal disturbance of the neuronal environment. The sample volumes are exceedingly small, on the order of tens of microliters. This is countered by the purity of the samples, reducing the need for extraction prior to assay. We present a HPLC ...

Science (New York, N.Y.), Jan 11, 2002

The motor abnormalities of Parkinson's disease (PD) are caused by alterations in basal gangli... more The motor abnormalities of Parkinson's disease (PD) are caused by alterations in basal ganglia network activity, including disinhibition of the subthalamic nucleus (STN), and excessive activity of the major output nuclei. Using adeno-associated viral vector-mediated somatic cell gene transfer, we expressed glutamic acid decarboxylase (GAD), the enzyme that catalyzes synthesis of the neurotransmitter GABA, in excitatory glutamatergic neurons of the STN in rats. The transduced neurons, when driven by electrical stimulation, produced mixed inhibitory responses associated with GABA release. This phenotypic shift resulted in strong neuroprotection of nigral dopamine neurons and rescue of the parkinsonian behavioral phenotype. This strategy suggests that there is plasticity between excitatory and inhibitory neurotransmission in the mammalian brain that could be exploited for therapeutic benefit.

Molecular Therapy — Methods & Clinical Development, 2014

Adipose tissue plays an essential role in metabolic homeostasis and holds promise as an alternati... more Adipose tissue plays an essential role in metabolic homeostasis and holds promise as an alternative depot organ in gene therapy. However, efficient methods of gene transfer into adipose tissue in vivo have yet to be established. Here, we assessed the transduction efficiency to fat depots by a family of novel engineered hybrid capsid serotypes (Rec1~4) recombinant adeno-associated viral (AAV) vectors in comparison with natural serotypes AAV1, AAV8, and AAV9. Rec2 serotype led to widespread transduction in both brown fat and white fat with the highest efficiency among the seven serotypes tested. As a proof-of-efficacy, Rec2 serotype was used to deliver Cre recombinase to adipose tissues of insulin receptor floxed animals. Insulin receptor knockdown led to decreased fat pad mass and morphological and molecular changes in the targeted depot. These novel hybrid AAV vectors can serve as powerful tools to genetically manipulate adipose tissue and provide valuable vehicles to gene therapy targeting adipose tissue.

Journal of Neuroscience, 2009

Recent evidence suggests that abnormal activation of cyclin-dependent kinase 5 (cdk5) is a critic... more Recent evidence suggests that abnormal activation of cyclin-dependent kinase 5 (cdk5) is a critical prodeath signal in stroke. However, the mechanism(s) by which cdk5 promotes death is unclear. Complicating the role of cdk5 are the observations that cdk5 can exist in multiple cellular regions and possess both prosurvival and prodeath characteristics. In particular, the critical role of cytoplasmic or nuclear cdk5 in neuronal jury, in vivo, is unclear. Therefore, we determined where cdk5 was activated in models of ischemia and how manipulation of cdk5 in differing compartments may affect neuronal death. Here, we show a critical function for cytoplasmic cdk5 in both focal and global models of stroke, in vivo. Cdk5 is activated in the cytoplasm and expression of DNcdk5 localized to the cytoplasm is protective. Importantly, we also demonstrate the antioxidant enzyme Prx2 (peroxiredoxin 2) as a critical cytoplasmic target of cdk5. In contrast, the role of cdk5 in the nucleus is context-dependent. Following focal ischemia, nuclear cdk5 is activated and functionally relevant while there is no evidence for such activation following global ischemia. Importantly, myocyte enhancer factor 2D (MEF2D), a previously described nuclear target of cdk5 in vitro, is also phosphorylated by cdk5 following focal ischemia. In addition, MEF2D expression in this paradigm ameliorates death. Together, our results address the critical issue of cdk5 activity compartmentalization, as well as define critical substrates for both cytoplasmic and nuclear cdk5 activity in adult models of stroke.

Proceedings of the National Academy of Sciences, 2006

cAMP response element-binding protein (CREB) is important for the formation and facilitation of l... more cAMP response element-binding protein (CREB) is important for the formation and facilitation of long-term memory in diverse models. However, to our knowledge, involvement of CREB in age-associated memory impairment has not been reported. Here, we use a recombinant adeno-associated virus vector to obtain stable transgenic expression of CREB as well as the inducible cAMP early repressor (ICER) in the hippocampus of adult rats. In a longitudinal study, we show that somatic gene transfer of both CREB and ICER does not alter long-term memory in young (3month-old) rats. However, at 15 months of age, the same CREBtransduced rats show significantly better long-term memory in spatial-navigation and passive-avoidance tasks compared with their equally aged control littermates, and a threshold effect is evident. In contrast, the aged ICER-transduced rats demonstrate significantly reduced memory in comparison with the same control group. Hippocampal CREB gene transfer prevented the agingrelated decrease in long-term memory found in the control rats. These data suggest that elevation of CREB protein levels in a subset of hippocampal neurons as achieved by somatic cell gene transfer might compensate for general deficits in molecular mechanisms underlying age-related memory loss in rats and, therefore, attenuate long-term-memory impairment during normal aging. adeno-associated virus vector ͉ inducible cAMP early repressor ͉ long-term memory ͉ hippocampus Conflict of interest statement: No conflicts declared.

Proceedings of the National Academy of Sciences, 1993

Signal-transduction pathways mediate a wide range of short-term changes in the physiology of neur... more Signal-transduction pathways mediate a wide range of short-term changes in the physiology of neuronal systems from invertebrates to mammals. However, examples of long-term changes in neuronal physiology mediated by these pathways have been limited to invertebrate systems. In this report, long-term changes in the physiology of mammalian neurons were studied by using genetic intervention to cause a long-lasting activation of the cAMP pathway. The catalytic domain of yeast adenylate cyclase (cyr), encoding a constitutive enzyme activity, was expressed in neuronal cells infected with a defective herpes simplex virus vector (pHSVcyr). In PC-12 cells infected with pHSVcyr, increases were seen in cAMP levels, protein kinase A activity, protein phosphorylation, phosphorylation of the tyrosine hydroxylase protein kinase A site (Ser4"), and catecholamine release. Infection of sympathetic neurons with pHSVcyr increased cAMP levels, protein phosphorylation, and catecholamine release. Yeast adenylate cyclase immunoreactivity and elevated cAMP levels were localized to the cell bodies of sympathetic neurons. The increase in neurotransmitter release was both Ca2+and activitydependent and persisted for at least 1 week after infection of the sympathetic neurons, suggesting that sustaned physiological activation of the cAMP pathway may mediate long-term changes in the neuronal physiology of mammalian systems.

Pediatric Research, 1993

to ensure normoxia [arterial oxygen tension > 100 mm Hg (> 13.3 pital of St. Raphael. 1450 Chapel... more to ensure normoxia [arterial oxygen tension > 100 mm Hg (> 13.3 pital of St. Raphael. 1450 Chapel St.. New Haven. CT 065 1 1. Supported in part by NIH Grants NS ROI-24605 (R,S,K,Y,) and NS-2x227 kPa)l and [arterial dioxide tension* 30-40 (M.J.D.). mm Hg (4.0-5.3 kPa)]. Blood glucose and blood lactate were ' Presented in part at the Child Neurology Society. Portland. OR. October 1991. monitored with a Beckman Glucose Analyzer I1 (Beckman In

Neuron, 2011

During development there is an activity-dependent switch in synaptic NMDA receptor subunit compos... more During development there is an activity-dependent switch in synaptic NMDA receptor subunit composition from predominantly GluN2B to GluN2A, though the precise role of this switch remains unknown. By deleting GluN2 subunits in single neurons during synaptogenesis, we find both GluN2B and GluN2A suppress AMPA receptor expression, albeit by distinct means. Similar to GluN1, GluN2B deletion increases the number of functional synapses, while GluN2A deletion increases the strength of unitary connections without affecting the number of functional synapses. We propose a model of excitatory synapse maturation in which baseline activation of GluN2Bcontaining receptors prevents premature synapse maturation until correlated activity allows induction of functional synapses. This activity also triggers the switch to GluN2A which dampens further potentiation. Furthermore, we analyze the subunit composition of synaptic NMDA receptors in CA1 pyramidal cells, provide electrophysiological evidence for a large population of synaptic triheteromeric receptors, and estimate the subunit-dependent open probability.

Neuron, 2004

mimicking the cocaine-induced reduction in Homer1 Medical University of South Carolina gene expre... more mimicking the cocaine-induced reduction in Homer1 Medical University of South Carolina gene expression by infusing antisense oligonucleotides Charleston, South Carolina 29425 into the accumbens sensitizes drug-naive rats to the 2 Department of Neuroscience motor stimulant effects of cocaine (Ghasemzadeh et al., The Johns Hopkins University School of Medicine 2003). Also, cocaine induces a rapid induction of the Baltimore, Maryland 21205 immediate early gene form of Homer1, and this gene 3 Department of Molecular Medicine and Pathology is remarkably dynamic during behavioral responses to University of Auckland environmental stimuli (Brakeman et al., 1997; Vazdarja-Auckland 1020 nova et al., 2002). These findings pose a hypothesis that New Zealand genetic or environmental alterations in the expression 4 Department of Psychiatry or function of one of the three Homer genes may affect Center for Drug and Alcohol Programs addiction to cocaine. Medical University of South Carolina Homer proteins are encoded by three genes (Homer1-3) Charleston, South Carolina 29425 and act to coordinate synaptic proteins for a variety of functions, including calcium signaling (Shin et al., 2003; Yuan et al., 2003), glutamate receptor signaling/traffick-Summary ing (Shiraishi et al., 2003; Xiao et al., 2000), and activitydependent synaptic remodeling (Sala et al., 2003; Usui Drug addiction involves complex interactions between et al., 2003). The multiple contributions to cellular hopharmacology and learning in genetically susceptible meostasis and plasticity by Homer proteins appear to be individuals. Members of the Homer gene family are mediated by a simple bimodal structure. The N-terminal regulated by acute and chronic cocaine adminis-Ena/VASP homology 1 (EVH1) domain mediates selectration. Here, we report that deletion of Homer1 or tive binding to other synaptic proteins, while the C-ter-Homer2 in mice caused the same increase in sensitivminal coiled-coil domain mediates self-association (Xiao ity to cocaine-induced locomotion, conditioned reet al., 2000). Among the proteins that bind to Homer ward, and augmented extracellular glutamate in nuare group I metabotropic glutamate receptors (mGluR1/5), cleus accumbens as that elicited by withdrawal from inositol-1,4,5-triphosphate (IP3) receptors, TRP cation repeated cocaine administration. Moreover, adenochannels, and Shank, which cluster with many proteins associated virus-mediated restoration of Homer2 in regulating synaptic plasticity, such as F-actin, dynamin3, the accumbens of Homer2 KO mice reversed the cocortactin, and NMDA (NR2B) and AMPA (GluR1) recepcaine-sensitized phenotype. Further analysis of Homer2 tors (Naisbitt et al., 1999; Shiraishi et al., 2003; Usui et KO mice revealed extensive additional behavioral and al., 2003; Yuan et al., 2003). The formation of Homerneurochemical similarities to cocaine-sensitized anidependent protein complexes is regulated in part by an mals, including accelerated acquisition of cocaine alternative transcript of Homer1 (Homer1a) that lacks self-administration and altered regulation of glutathe coiled-coil domain and the ability to multimerize mate by metabotropic glutamate receptors and cys-(Bottai et al., 2002; Xiao et al., 2000). Homer1a is induced tine/glutamate exchange. These data show that Homer by synaptic activity as an immediate early gene product, deletion mimics the behavioral and neurochemical functions as a natural dominant negative of Homer phenotype produced by repeated cocaine administramultimers, and has been shown to influence synaptic tion and implicate Homer in regulating addiction to coplasticity (Brakeman et al., 1997; Hennou et al., 2003; caine. Sala et al., 2003). In order to test the hypothesis that the regulation of

Movement Disorders, 2006

This activity has been planned and implemented in accordance with the Essential Areas and Policie... more This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through joint sponsorship of The Movement Disorder Society and the Parkinson Study Group. The Movement Disorder Society is accredited by the ACCME to provide continuing medical education for physicians. The symposia will consist of peer-reviewed platform and poster presentations designed to communicate recent research advances in the field of Parkinson's disease, Huntington's disease, ataxia, dystonia, myoclonus, Tourette's syndrome, tremor and other Movement Disorders to professionals in neurology and related disciplines. Practitioners, educators, and researchers are invited to attend. Abstracts of platform and poster presentations representing original material will be published in the September 2006 issue of Movement Disorders. At the conclusion of this session, participants should be able to: 1) Identify by scholarly review, oral presentation and group discussion the current research into the diagnosis, prevention and treatment of Parkinson's disease and other Movement Disorders; 2) Identify the important advances in research and clinical treatments relating to a variety of Movement Disorders; 3) Discuss new pharmacological and non-pharmacological treatment options available for Parkinson's disease and other Movement Disorders; 4) Identify the mechanisms (genetic, environmental, pathophysiology, neurobiology) linked to Parkinson's disease and other Movement Disorders; and 5) Discuss the diagnostic approaches and tools available for Parkinson's disease and other Movement Disorders.

Methods, 2002

Since the first demonstration of central nervous system (CNS) transduction with recombinant adeno... more Since the first demonstration of central nervous system (CNS) transduction with recombinant adeno-associated virus, improvements in vector production and promoter strength have lead to dramatic increases in the number of cells transduced and the level of expression within each cell. The improvements in promoter strength have resulted from a move away from the original cytomegalovirus (CMV) promoter toward the use of hybrid CMV-based promoters and constitutive cellular promoters. This review summarizes and compares different promoters and regulatory elements that have been used with rAAV as a reference toward achieving a high level of rAAV-mediated transgene expression in the CNS.

Glia, 1993

Immunostaining and high-pressure liquid chromatography (HPLC) were used to study the developmenta... more Immunostaining and high-pressure liquid chromatography (HPLC) were used to study the developmental time course of astrocytic gamma-aminobutyric acid (GABA) expression in rat optic nerve. GABA immunostaining was carried out on cultured astrocytes, and on whole optic nerve. Confocal scanning laser microscopy was used to obtain optical sections in excised whole tissue in order to localize the cellular origins of GABA within the relatively intact optic nerve. GABA immunoreactivity was localized in astrocytes identified by GFAP staining; GABA staining was most intense in early neonatal optic nerve and attenuated over 3 weeks of postnatal development. The staining was pronounced in the astrocyte cell bodies and processes but not in the nucleus. There was a paucity of GABA immunoreactivity by postnatal day 20, both in culture and in whole optic nerve. A biochemical assay for optic nerve GABA using HPLC indicated a relatively high concentration of GABA in the neonate, which rapidly attenuated over the first 3 postnatal weeks. Immunoreactivity for the GABA synthesis enzyme glutamic acid decarboxylase (GAD) was pronounced in neonates but also attenuated with development. These results indicate that GABA and the GABA synthesis enzyme GAD are localized in astrocytes of optic nerve, and that their expression is transient during postnatal development.