Rob Cassidy | Dawson College (original) (raw)

Papers by Rob Cassidy

Journal of Comparative Neurology, 2013

Prior studies have identified two anatomically and neurochemically distinct cellular compartments... more Prior studies have identified two anatomically and neurochemically distinct cellular compartments within the mammalian striatum, termed striosomes and matrix, which express μ-opioid receptors (μOR) and EphA4, respectively. Here we identify and characterize an additional compartment in the rat striatum composed of neurons that express EphA7. In situ hybridization and immunohistochemical data indicate that neurons expressing EphA7 mRNA and protein are arranged in a banded “matrisome-like” pattern confined to the matrix in the dorsal striatum. Within the ventral striatum, EphA7-positive (+) neurons have a less organized mosaic pattern that partially overlaps areas expressing μOR. Immunolabeling data demonstrate that EphA7+striatofugal axons form distinct fascicles leaving the striatum. Within the globus pallidus, EphA7+ axons terminate primarily within ventromedial areas of the nucleus and along its striatal border. EphA7+ axons avoid regions containing dopamine neurons within the substantia nigra and preferentially innervate areas near the rostral and caudal margins of the nucleus. Within both nuclei, EphA7+ axons have similar but more restricted terminal fields than the entire population of EphA4+ matrix axons, indicating that EphA7+axons comprise a subpopulation of matrix axons. Ligand binding data demonstrate that ephrin-A5 selectively binds areas of the striatum, globus pallidus and substantia nigra containing EphA7+ neurons and axons, but not areas expressing only EphA4. Our findings demonstrate that EphA7 expression identifies a novel “matrisome” compartment within the matrix that binds ephrin-A5 and possesses unique axonal projections. Our findings also suggest that EphA7 and ephrin-A5 may participate in the formation of this matrisome subcompartment and its striatofugal projections.

Proceedings of Informing Science & IT Education Conference (InSITE), 2012

A Classroom Response System (CRS) was adopted in an introductory business statistics course for t... more A Classroom Response System (CRS) was adopted in an introductory business statistics course for the first time. This paper reports on the reflections on this experience by the professor teaching this course and feedback and contributions of the other members of the research team. It begins by presenting a theoretical foundation for the use of CRS and proceeds to a rationale for its adoption in statistics courses. A detailed description of how CRS was used in this particular course is provided and lessons learned are discussed in light of the relevant research literature. We hope that our reflections and lessons learned will raise awareness among faculty members
contemplating using CRS, especially those in introductory statistics, about issues that might be encountered the first time around and help them be more proactive in their initial use of CRS.

Computer Technology and Application, Jan 2013

The use of clicker technology as a tool for promoting learning, let along deep learning, is hotly... more The use of clicker technology as a tool for promoting learning, let along deep learning, is hotly debated and has its proponents and opponents. With the question still open, this paper examines the use of this technology in fostering critical thinking and other higher-order learning and team-building skills, in the context of two entry-level psychology courses. The results obtained indicate that from the perspectives of both the student and the instructor, the integration of this technology was positively perceived to enhance the learning process and the acquisition of these skills. It would seem these concepts are, after all, not antithetical.

Proceedings of the IADIS International Conference on Cognition and Exploratory Learning in Digital Age, 2009

This paper examines the use of clicker technology in fostering critical thinking and other higher... more This paper examines the use of clicker technology in fostering critical thinking and other higher-order learning and team-building skills, in the context of two entry-level psychology courses. The results obtained indicate that from the perspectives of both the student and the instructor, the integration of this technology was positively perceived to enhance the learning process and the acquisition of these skills.

Neuron, 2009

Delineating the molecular basis of synapse development is crucial for understanding brain functio... more Delineating the molecular basis of synapse development is crucial for understanding brain function. Cocultures of neurons with transfected fibroblasts have demonstrated the synapse-promoting activity of candidate molecules. Here, we performed an unbiased expression screen for synaptogenic proteins in the coculture assay using custom-made cDNA libraries. Reisolation of NGL-3/LRRC4B and neuroligin-2 accounts for a minority of positive clones, indicating that current understanding of mammalian synaptogenic proteins is incomplete. We identify LRRTM1 as a transmembrane protein that induces presynaptic differentiation in contacting axons. All four LRRTM family members exhibit synaptogenic activity, LRRTMs localize to excitatory synapses, and artificially induced clustering of LRRTMs mediates postsynaptic differentiation. We generate LRRTM1–/– mice and reveal altered distribution of the vesicular glutamate transporter VGLUT1, confirming an in vivo synaptic function. These results suggest a prevalence of LRR domain proteins in trans-synaptic signaling and provide a cellular basis for the reported linkage of LRRTM1 to handedness and schizophrenia.

Nature Neuroscience, 2009

Neurons are continuously generated from stem cells in discrete regions in the adult mammalian bra... more Neurons are continuously generated from stem cells in discrete regions in the adult mammalian brain. We found that ependymal cells lining the lateral ventricles were quiescent and did not contribute to adult neurogenesis under normal conditions in mice but instead gave rise to neuroblasts and astrocytes in response to stroke. Ependymal cell quiescence was actively maintained by canonical Notch signaling. Inhibition of this pathway in uninjured animals allowed ependymal cells to enter the cell cycle and produce olfactory bulb neurons, whereas forced Notch signaling was sufficient to block the ependymal cell response to stroke. Ependymal cells were depleted by stroke and failed to self-renew sufficiently to maintain their own population. Thus, although ependymal cells act as primary cells in the neural lineage to produce neurons and glial cells after stroke, they do not fulfill defining criteria for stem cells under these conditions and instead serve as a reservoir that is recruited by injury.

Current Biology, 2002

Over the past decade, it has become clear that neural stem cells in the adult mammalian brain con... more Over the past decade, it has become clear that neural stem cells in the adult mammalian brain continuously generate new neurons, predominantly in the hippocampus and olfactory bulb [1]. However, the central issue of whether these new neurons participate in functional synaptic circuitry has yet to be resolved. Here, we use virus-based transsynaptic neuronal tracing and c-Fos mapping of odor-induced neuronal activity to demonstrate that neurons generated in the adult functionally integrate into the synaptic circuitry of the brain.

Genes & Development, 2005

The number of cells in an organ is regulated by mitogens and trophic factors that impinge on intr... more The number of cells in an organ is regulated by mitogens and trophic factors that impinge on intrinsic determinants of proliferation and apoptosis. We here report the identification of an additional mechanism to control cell number in the brain: EphA7 induces ephrin-A2 reverse signaling, which negatively regulates neural progenitor cell proliferation. Cells in the neural stem cell niche in the adult brain proliferate more and have a shorter cell cycle in mice lacking ephrin-A2. The increased progenitor proliferation is accompanied by a higher number of cells in the olfactory bulb. Disrupting the interaction between ephrin-A2 and EphA7 in the adult brain of wild-type mice disinhibits proliferation and results in increased neurogenesis. The identification of ephrin-A2 and EphA7 as negative regulators of progenitor cell proliferation reveals a novel mechanism to control cell numbers in the brain.

Proc of the Natl Acad Sciences, 2003

New neurons are generated from stem cells in a few regions of the adult mammalian brain. Here we ... more New neurons are generated from stem cells in a few regions of the adult mammalian brain. Here we provide evidence for the generation of dopaminergic projection neurons of the type that are lost in Parkinson's disease from stem cells in the adult rodent brain and show that the rate of neurogenesis is increased after a lesion. The number of new neurons generated under physiological conditions in substantia nigra pars compacta was found to be several orders of magnitude smaller than in the granular cell layer of the dentate gyrus of the hippocampus. However, if the rate of neuronal turnover is constant, the entire population of dopaminergic neurons in substantia nigra could be replaced during the lifespan of a mouse. These data indicate that neurogenesis in the adult brain is more widespread than previously thought and may have implications for our understanding of the pathogenesis and treatment of neurodegenerative disorders such as Parkinson's disease.

The majority of neurons are born before or around birth. The first indications of neurogenesis in the adult mammalian brain were presented four decades ago, but it is only during the last years that it has been firmly established that new neurons are generated continuously from stem cells in certain regions of the adult brain in all studied mammals, including man (1–3). The most active neurogenic regions are the dentate gyrus (DG) of the hippocampus and the olfactory bulb. It has been estimated that ≈10,000 new neurons are added each day to the adult rat DG (4), and the rate of neurogenesis in the olfactory bulb is likely to be severalfold higher. In retrospect, it is quite remarkable that such pronounced processes went unnoticed for so long time, and it raises the question whether there may be a low level of neurogenesis in other brain regions, which has not yet been detected.

In addition to the neurogenesis in the olfactory bulb and DG, low numbers of new neurons have been suggested to be generated in other parts of the hippocampus as well as in the cortex (5–6), although the latter remains controversial (7). Moreover, neurogenesis has been demonstrated in several additional regions in response to injury (8–11).

We asked whether new neurons are generated also in the substantia nigra pars compacta (SNpc) of the midbrain, the region where dopamine-producing neurons lost in Parkinson's disease reside. We here report evidence for a slow turnover of dopaminergic projection neurons in the adult rodent brain, and that neurogenesis is increased after a partial injury.

Current Biology, 2002

Embryonic stem cells readily generate neurons in vitro, but steering their differentiation into s... more Embryonic stem cells readily generate neurons in vitro, but steering their differentiation into specific neuronal subtypes is a major challenge. It has now been shown that mechanisms that regulate neuronal specification during development can be applied to embryonic stem cells in vitro; this may lead to new ways of generating cells for therapy.

Nature, 2001

"Stem cells have great potential for treating a variety of diseases and seem to hit the headlines... more "Stem cells have great potential for treating a variety of diseases and seem to hit the headlines almost every week. An extremely pure population of brain stem cells has now been obtained from adult mice.

Many of us were taught in school that we are born with a certain number of nerve cells, which cannot renew themselves. But, after some initial indications in the 1960s, it is now known that our brains are much more capable of change than was previously thought, and that neurons are continuously replenished in some regions of the adult brain."

Experimental Cell Research, 2002

Neural stem cells may present an ideal route for gene therapy as well as offer new possibilities ... more Neural stem cells may present an ideal route for gene therapy as well as offer new possibilities for the replacement of neurons lost to injury or disease. However, it has proved difficult to express ectopic genes in stem cells. We report methods to introduce genes into adult neural stem cells using viral and nonviral vectors in vitro and in vivo. Adenoviral and VSV-G-pseudotyped retroviral vectors are more efficient than plasmid transfection or VSV-G lentiviral transduction in vitro. We further show that adult neural stem cells can be directed to a neuronal fate by ectopic expression of neurogenin 2 in vitro. Plasmids can be delivered in vivo when complexed with linear polyethyleneimine, and gene expression can be targeted specifically to neural stem or progenitor cells by the use of specific promoters. These techniques may be utilized both to study the function of various genes in the differentiation of neural stem cells to specific cell fates and, ultimately, for gene therapy or to generate specific differentiated progeny for cell transplantation.

The Journal of Neuroscience, 1999

The striatum integrates limbic and neocortical inputs to regulate sensorimotor and psychomotor be... more The striatum integrates limbic and neocortical inputs to regulate sensorimotor and psychomotor behaviors. This function is dependent on the segregation of striatal projection neurons into anatomical and functional components, such as the striosome and matrix compartments. In the present study the association of ephrin-A cell surface ligands and EphA receptor tyrosine kinases (RTKs) with the organization of these compartments was determined in postnatal rats. Ephrin-A1 and ephrin-A4 selectively bind to EphA receptors on neurons restricted to the matrix compartment. Binding is absent from the striosomes, which were identified by μ-opioid receptor immunostaining. In contrast, ephrin-A2, ephrin-A3, and ephrin-A5 exhibit a different mosaic binding pattern that appears to define a subset of matrix neurons. In situ hybridization for EphA RTKs reveals that the two different ligand binding patterns strictly match the mRNA expression patterns of EphA4 and EphA7. Ligand–receptor binding assays indicate that ephrin-A1 and ephrin-A4 selectively bind EphA4 but not EphA7 in the lysates of striatal tissue. Conversely, ephrin-A2, ephrin-A3, and ephrin-A5 bind EphA7 but not EphA4. These observations implicate selective interactions between ephrin-A molecules and EphA RTKs as potential mechanisms for regulating the compartmental organization of the striatum.

The Journal of Neuroscience, 1998

"Limbic motor seizures in animals, analogous to complex partial seizures in humans, result in a c... more "Limbic motor seizures in animals, analogous to complex partial seizures in humans, result in a consistent activation of the mediodorsal thalamus (MD) and, with prolonged seizures, damage to MD. This study examined the functional role of MD in focally evoked limbic motor seizures in the rat. GABA- and glutamate (Glu)-mediated synaptic transmissions in MD were evaluated for an influence on seizures evoked from area tempestas (AT), a discrete epileptogenic site in the rostral piriform cortex.

A GABAA receptor agonist, Glu receptor antagonists, or a GABA-elevating agent were focally microinfused into MD before evoking seizures by focal application of bicuculline methiodide into the ipsilateral AT. Focal pretreatment of MD with the GABAAagonist muscimol (190 pmol) protected against seizures evoked from AT. Seizure protection was also obtained with the focal application of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (500 pmol), an antagonist of the AMPA subtype of Glu receptors, into MD. In contrast, focal pretreatment of MD with a competitive antagonist of the NMDA receptor 2-amino-7-phosphonoheptanoic acid (500 pmol) did not attenuate seizures. The anticonvulsant effects achieved with intra-MD injections of muscimol and NBQX were site-specific, because no seizure protection was obtained with injections placed 2 mm ventral or lateral to MD. Prolonged seizure protection was obtained following GABA elevation in MD after the application of the GABA transaminase inhibitor vigabatrin (194 nmol). These results suggest the following: (1) MD is a critical participant in the generation of seizures elicited focally from piriform cortex; (2) transmission via AMPA receptors, but not NMDA receptors, in MD regulates limbic seizure propagation; and (3) a GABA-mediated system exists within MD, the enhancement of which protects against focally evoked limbic motor seizures."

Journal of Comparative Neurology, 2013

Prior studies have identified two anatomically and neurochemically distinct cellular compartments... more Prior studies have identified two anatomically and neurochemically distinct cellular compartments within the mammalian striatum, termed striosomes and matrix, which express μ-opioid receptors (μOR) and EphA4, respectively. Here we identify and characterize an additional compartment in the rat striatum composed of neurons that express EphA7. In situ hybridization and immunohistochemical data indicate that neurons expressing EphA7 mRNA and protein are arranged in a banded “matrisome-like” pattern confined to the matrix in the dorsal striatum. Within the ventral striatum, EphA7-positive (+) neurons have a less organized mosaic pattern that partially overlaps areas expressing μOR. Immunolabeling data demonstrate that EphA7+striatofugal axons form distinct fascicles leaving the striatum. Within the globus pallidus, EphA7+ axons terminate primarily within ventromedial areas of the nucleus and along its striatal border. EphA7+ axons avoid regions containing dopamine neurons within the substantia nigra and preferentially innervate areas near the rostral and caudal margins of the nucleus. Within both nuclei, EphA7+ axons have similar but more restricted terminal fields than the entire population of EphA4+ matrix axons, indicating that EphA7+axons comprise a subpopulation of matrix axons. Ligand binding data demonstrate that ephrin-A5 selectively binds areas of the striatum, globus pallidus and substantia nigra containing EphA7+ neurons and axons, but not areas expressing only EphA4. Our findings demonstrate that EphA7 expression identifies a novel “matrisome” compartment within the matrix that binds ephrin-A5 and possesses unique axonal projections. Our findings also suggest that EphA7 and ephrin-A5 may participate in the formation of this matrisome subcompartment and its striatofugal projections.

Proceedings of Informing Science & IT Education Conference (InSITE), 2012

A Classroom Response System (CRS) was adopted in an introductory business statistics course for t... more A Classroom Response System (CRS) was adopted in an introductory business statistics course for the first time. This paper reports on the reflections on this experience by the professor teaching this course and feedback and contributions of the other members of the research team. It begins by presenting a theoretical foundation for the use of CRS and proceeds to a rationale for its adoption in statistics courses. A detailed description of how CRS was used in this particular course is provided and lessons learned are discussed in light of the relevant research literature. We hope that our reflections and lessons learned will raise awareness among faculty members
contemplating using CRS, especially those in introductory statistics, about issues that might be encountered the first time around and help them be more proactive in their initial use of CRS.

Computer Technology and Application, Jan 2013

The use of clicker technology as a tool for promoting learning, let along deep learning, is hotly... more The use of clicker technology as a tool for promoting learning, let along deep learning, is hotly debated and has its proponents and opponents. With the question still open, this paper examines the use of this technology in fostering critical thinking and other higher-order learning and team-building skills, in the context of two entry-level psychology courses. The results obtained indicate that from the perspectives of both the student and the instructor, the integration of this technology was positively perceived to enhance the learning process and the acquisition of these skills. It would seem these concepts are, after all, not antithetical.

Proceedings of the IADIS International Conference on Cognition and Exploratory Learning in Digital Age, 2009

This paper examines the use of clicker technology in fostering critical thinking and other higher... more This paper examines the use of clicker technology in fostering critical thinking and other higher-order learning and team-building skills, in the context of two entry-level psychology courses. The results obtained indicate that from the perspectives of both the student and the instructor, the integration of this technology was positively perceived to enhance the learning process and the acquisition of these skills.

Neuron, 2009

Delineating the molecular basis of synapse development is crucial for understanding brain functio... more Delineating the molecular basis of synapse development is crucial for understanding brain function. Cocultures of neurons with transfected fibroblasts have demonstrated the synapse-promoting activity of candidate molecules. Here, we performed an unbiased expression screen for synaptogenic proteins in the coculture assay using custom-made cDNA libraries. Reisolation of NGL-3/LRRC4B and neuroligin-2 accounts for a minority of positive clones, indicating that current understanding of mammalian synaptogenic proteins is incomplete. We identify LRRTM1 as a transmembrane protein that induces presynaptic differentiation in contacting axons. All four LRRTM family members exhibit synaptogenic activity, LRRTMs localize to excitatory synapses, and artificially induced clustering of LRRTMs mediates postsynaptic differentiation. We generate LRRTM1–/– mice and reveal altered distribution of the vesicular glutamate transporter VGLUT1, confirming an in vivo synaptic function. These results suggest a prevalence of LRR domain proteins in trans-synaptic signaling and provide a cellular basis for the reported linkage of LRRTM1 to handedness and schizophrenia.

Nature Neuroscience, 2009

Neurons are continuously generated from stem cells in discrete regions in the adult mammalian bra... more Neurons are continuously generated from stem cells in discrete regions in the adult mammalian brain. We found that ependymal cells lining the lateral ventricles were quiescent and did not contribute to adult neurogenesis under normal conditions in mice but instead gave rise to neuroblasts and astrocytes in response to stroke. Ependymal cell quiescence was actively maintained by canonical Notch signaling. Inhibition of this pathway in uninjured animals allowed ependymal cells to enter the cell cycle and produce olfactory bulb neurons, whereas forced Notch signaling was sufficient to block the ependymal cell response to stroke. Ependymal cells were depleted by stroke and failed to self-renew sufficiently to maintain their own population. Thus, although ependymal cells act as primary cells in the neural lineage to produce neurons and glial cells after stroke, they do not fulfill defining criteria for stem cells under these conditions and instead serve as a reservoir that is recruited by injury.

Current Biology, 2002

Over the past decade, it has become clear that neural stem cells in the adult mammalian brain con... more Over the past decade, it has become clear that neural stem cells in the adult mammalian brain continuously generate new neurons, predominantly in the hippocampus and olfactory bulb [1]. However, the central issue of whether these new neurons participate in functional synaptic circuitry has yet to be resolved. Here, we use virus-based transsynaptic neuronal tracing and c-Fos mapping of odor-induced neuronal activity to demonstrate that neurons generated in the adult functionally integrate into the synaptic circuitry of the brain.

Genes & Development, 2005

The number of cells in an organ is regulated by mitogens and trophic factors that impinge on intr... more The number of cells in an organ is regulated by mitogens and trophic factors that impinge on intrinsic determinants of proliferation and apoptosis. We here report the identification of an additional mechanism to control cell number in the brain: EphA7 induces ephrin-A2 reverse signaling, which negatively regulates neural progenitor cell proliferation. Cells in the neural stem cell niche in the adult brain proliferate more and have a shorter cell cycle in mice lacking ephrin-A2. The increased progenitor proliferation is accompanied by a higher number of cells in the olfactory bulb. Disrupting the interaction between ephrin-A2 and EphA7 in the adult brain of wild-type mice disinhibits proliferation and results in increased neurogenesis. The identification of ephrin-A2 and EphA7 as negative regulators of progenitor cell proliferation reveals a novel mechanism to control cell numbers in the brain.

Proc of the Natl Acad Sciences, 2003

New neurons are generated from stem cells in a few regions of the adult mammalian brain. Here we ... more New neurons are generated from stem cells in a few regions of the adult mammalian brain. Here we provide evidence for the generation of dopaminergic projection neurons of the type that are lost in Parkinson's disease from stem cells in the adult rodent brain and show that the rate of neurogenesis is increased after a lesion. The number of new neurons generated under physiological conditions in substantia nigra pars compacta was found to be several orders of magnitude smaller than in the granular cell layer of the dentate gyrus of the hippocampus. However, if the rate of neuronal turnover is constant, the entire population of dopaminergic neurons in substantia nigra could be replaced during the lifespan of a mouse. These data indicate that neurogenesis in the adult brain is more widespread than previously thought and may have implications for our understanding of the pathogenesis and treatment of neurodegenerative disorders such as Parkinson's disease.

The majority of neurons are born before or around birth. The first indications of neurogenesis in the adult mammalian brain were presented four decades ago, but it is only during the last years that it has been firmly established that new neurons are generated continuously from stem cells in certain regions of the adult brain in all studied mammals, including man (1–3). The most active neurogenic regions are the dentate gyrus (DG) of the hippocampus and the olfactory bulb. It has been estimated that ≈10,000 new neurons are added each day to the adult rat DG (4), and the rate of neurogenesis in the olfactory bulb is likely to be severalfold higher. In retrospect, it is quite remarkable that such pronounced processes went unnoticed for so long time, and it raises the question whether there may be a low level of neurogenesis in other brain regions, which has not yet been detected.

In addition to the neurogenesis in the olfactory bulb and DG, low numbers of new neurons have been suggested to be generated in other parts of the hippocampus as well as in the cortex (5–6), although the latter remains controversial (7). Moreover, neurogenesis has been demonstrated in several additional regions in response to injury (8–11).

We asked whether new neurons are generated also in the substantia nigra pars compacta (SNpc) of the midbrain, the region where dopamine-producing neurons lost in Parkinson's disease reside. We here report evidence for a slow turnover of dopaminergic projection neurons in the adult rodent brain, and that neurogenesis is increased after a partial injury.

Current Biology, 2002

Embryonic stem cells readily generate neurons in vitro, but steering their differentiation into s... more Embryonic stem cells readily generate neurons in vitro, but steering their differentiation into specific neuronal subtypes is a major challenge. It has now been shown that mechanisms that regulate neuronal specification during development can be applied to embryonic stem cells in vitro; this may lead to new ways of generating cells for therapy.

Nature, 2001

"Stem cells have great potential for treating a variety of diseases and seem to hit the headlines... more "Stem cells have great potential for treating a variety of diseases and seem to hit the headlines almost every week. An extremely pure population of brain stem cells has now been obtained from adult mice.

Many of us were taught in school that we are born with a certain number of nerve cells, which cannot renew themselves. But, after some initial indications in the 1960s, it is now known that our brains are much more capable of change than was previously thought, and that neurons are continuously replenished in some regions of the adult brain."

Experimental Cell Research, 2002

Neural stem cells may present an ideal route for gene therapy as well as offer new possibilities ... more Neural stem cells may present an ideal route for gene therapy as well as offer new possibilities for the replacement of neurons lost to injury or disease. However, it has proved difficult to express ectopic genes in stem cells. We report methods to introduce genes into adult neural stem cells using viral and nonviral vectors in vitro and in vivo. Adenoviral and VSV-G-pseudotyped retroviral vectors are more efficient than plasmid transfection or VSV-G lentiviral transduction in vitro. We further show that adult neural stem cells can be directed to a neuronal fate by ectopic expression of neurogenin 2 in vitro. Plasmids can be delivered in vivo when complexed with linear polyethyleneimine, and gene expression can be targeted specifically to neural stem or progenitor cells by the use of specific promoters. These techniques may be utilized both to study the function of various genes in the differentiation of neural stem cells to specific cell fates and, ultimately, for gene therapy or to generate specific differentiated progeny for cell transplantation.

The Journal of Neuroscience, 1999

The striatum integrates limbic and neocortical inputs to regulate sensorimotor and psychomotor be... more The striatum integrates limbic and neocortical inputs to regulate sensorimotor and psychomotor behaviors. This function is dependent on the segregation of striatal projection neurons into anatomical and functional components, such as the striosome and matrix compartments. In the present study the association of ephrin-A cell surface ligands and EphA receptor tyrosine kinases (RTKs) with the organization of these compartments was determined in postnatal rats. Ephrin-A1 and ephrin-A4 selectively bind to EphA receptors on neurons restricted to the matrix compartment. Binding is absent from the striosomes, which were identified by μ-opioid receptor immunostaining. In contrast, ephrin-A2, ephrin-A3, and ephrin-A5 exhibit a different mosaic binding pattern that appears to define a subset of matrix neurons. In situ hybridization for EphA RTKs reveals that the two different ligand binding patterns strictly match the mRNA expression patterns of EphA4 and EphA7. Ligand–receptor binding assays indicate that ephrin-A1 and ephrin-A4 selectively bind EphA4 but not EphA7 in the lysates of striatal tissue. Conversely, ephrin-A2, ephrin-A3, and ephrin-A5 bind EphA7 but not EphA4. These observations implicate selective interactions between ephrin-A molecules and EphA RTKs as potential mechanisms for regulating the compartmental organization of the striatum.

The Journal of Neuroscience, 1998

"Limbic motor seizures in animals, analogous to complex partial seizures in humans, result in a c... more "Limbic motor seizures in animals, analogous to complex partial seizures in humans, result in a consistent activation of the mediodorsal thalamus (MD) and, with prolonged seizures, damage to MD. This study examined the functional role of MD in focally evoked limbic motor seizures in the rat. GABA- and glutamate (Glu)-mediated synaptic transmissions in MD were evaluated for an influence on seizures evoked from area tempestas (AT), a discrete epileptogenic site in the rostral piriform cortex.

A GABAA receptor agonist, Glu receptor antagonists, or a GABA-elevating agent were focally microinfused into MD before evoking seizures by focal application of bicuculline methiodide into the ipsilateral AT. Focal pretreatment of MD with the GABAAagonist muscimol (190 pmol) protected against seizures evoked from AT. Seizure protection was also obtained with the focal application of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (500 pmol), an antagonist of the AMPA subtype of Glu receptors, into MD. In contrast, focal pretreatment of MD with a competitive antagonist of the NMDA receptor 2-amino-7-phosphonoheptanoic acid (500 pmol) did not attenuate seizures. The anticonvulsant effects achieved with intra-MD injections of muscimol and NBQX were site-specific, because no seizure protection was obtained with injections placed 2 mm ventral or lateral to MD. Prolonged seizure protection was obtained following GABA elevation in MD after the application of the GABA transaminase inhibitor vigabatrin (194 nmol). These results suggest the following: (1) MD is a critical participant in the generation of seizures elicited focally from piriform cortex; (2) transmission via AMPA receptors, but not NMDA receptors, in MD regulates limbic seizure propagation; and (3) a GABA-mediated system exists within MD, the enhancement of which protects against focally evoked limbic motor seizures."