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CURATOR
A pinboard by
Melissa Martin

I'm a Doctoral Candidate in the Biomedical Sciences PhD program at Florida State University

PINBOARD SUMMARY

Research related to GABA neurogenesis, differentiation, and migration during early brain development

Brain development is a process tightly regulated by signals from various neurotransmitters, and even small deviations in these signals can have a profound impact on overall development of the brain and behavior. A common theme underlying the etiology and patho-physiology of neurological and psychiatric disorders with developmental onset such as schizophrenia, ADHD, autism and early onset dystonia, is perturbation of the GABA neurotransmitter systems during brain development. Yet, little is known about the molecular mechanisms that underlie the pathology in these disorders.

During early embryonic corticogenesis, neurons migrate from the sites of origin near the ventricles to their final destinations via radial or tangential migratory pathways. In particular, virtually all GABA neurons of the dorsal forebrain are produced in the ganglionic eminence of the basal forebrain and migrate tangentially to regions of the dorsal forebrain.

The research in my lab aims to elucidate the mechanisms that underlie GABA migration during early brain development and to better understand how drugs of abuse can alter the GABAergic system during this both sensitive and critical period of brain development.

17 ITEMS PINNED

Development of projection-specific interneurons and projection neurons in the embryonic mouse and rat spinal cord.

Abstract: Interneurons and projection neurons in the lumbar spinal cord of mouse and rat embryos were labeled retrogradely with fluorescent dextran amines from a distance of one segment from the segment of origin [lumbar segment (L) 2]. Six classes with specific axonal projections (ipsilateral ascending, descending, and bifurcating, and commissural ascending, descending, and bifurcating) were identified by differential labeling in both species and followed from embryonic day (E)12 to birth in the mouse. Neurons with shorter projections (intrasegmental interneurons) were not studied. We show that the four nonbifurcating neuron classes occupy characteristic, partially overlapping domains in the transverse plane, indicating a systematic pattern of migration and settlement related to axon trajectories. The number of neurons in each of the nonbifurcating classes increased steadily during development. Bifurcating neurons represented a minor fraction of the total throughout development and had relatively scattered positions within the ipsilateral and commissural neuron domains. Combination of retrograde tracing and immunohistochemistry for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) showed that none of the spinal neurons in the six projection-specific classes was GABA positive, suggesting that all GABA-positive spinal neurons, including previously described GABA-positive commissural neurons, are unlikely to have projections exceeding one or two segments in either direction.

Pub.: 27 Jan '05, Pinned: 31 Aug '17

Dynamic Changes from Depolarizing to Hyperpolarizing GABAergic Actions during Giant Depolarizing Potentials in the Neonatal Rat Hippocampus.

Abstract: During development, GABA exerts depolarizing action on immature neurons and, acting in synergy with glutamate, drives giant depolarizing potentials (GDPs) in the hippocampal network. Yet, blockade of the GABA(A) receptors transforms GDPs to epileptiform discharges suggesting dual, both excitatory and inhibitory, actions of GABA in the immature hippocampal network. However, the nature of this dualism in early GABA actions is poorly understood. Here we characterized the dynamics of synaptic currents mediated by GABA(A) and glutamate receptors through an estimation of the changes in their conductance and driving forces in neonatal rat CA3 pyramidal cells during GDPs. We found that depolarizing GABAergic and glutamatergic currents act in synergy at the GDPs' onset. However, during the peak of the population discharge, the inward synaptic current was essentially mediated by glutamate receptors whereas GABA currents transiently switched their direction from depolarizing to hyperpolarizing as a result of neuronal depolarization above the GABA(A) reversal potential. Thus, the action of GABA on CA3 pyramidal cells dynamically changes during GDPs from excitatory at the GDPs' onset to inhibitory at the GDPs' peak. We propose that the dynamic changes in GABA actions occurring during GDPs enable GABAergic interneurons not only to initiate the discharge of pyramidal cells but also to control excitation in the recurrent CA3 network preventing epileptiform synchronization.During development GABA exerts a depolarizing action on immature neurons. However, at the network level the effects of GABA are complex involving both excitatory and inhibitory actions. Here we show that GABA actions critically depend on the network state. Although GABA depolarizes neurons at rest and at the onset of population bursts, it transiently becomes hyperpolarizing at the peak of the population bursts. These dynamic changes in GABA actions enable GABAergic interneurons not only to initiate the network discharge but also to control excitation to prevent epileptiform synchronization.

Pub.: 18 Sep '15, Pinned: 31 Aug '17

Interneurons Differentially Contribute to Spontaneous Network Activity in the Developing Hippocampus Dependent on Their Embryonic Lineage.

Abstract: Spontaneously generated network activity is a hallmark of developing neural circuits, and plays an important role in the formation of synaptic connections. In the rodent hippocampus, this activity is observed in vitro as giant depolarizing potentials (GDPs) during the first postnatal week. Interneurons importantly contribute to GDPs, due to the depolarizing actions of GABA early in development. While they are highly diverse, cortical interneurons can be segregated into two distinct groups based on their embryonic lineage from either the medial or caudal ganglionic eminences (MGE and CGE). There is evidence suggesting CGE-derived interneurons are important for GDP generation; however, their contribution relative to those from the MGE has never been directly tested. Here, we optogenetically inhibited either MGE- or CGE-derived interneurons in a region-specific manner in mouse neonatal hippocampus in vitro. In CA1, where interneurons are the primary source of recurrent excitation, we found that those from the MGE strongly and preferentially contributed to GDP generation. Furthermore, in dual whole-cell patch recordings in neonatal CA1, MGE interneurons formed synaptic connections to and from neighboring pyramidal cells at a much higher rate than those from the CGE. These MGE interneurons were commonly perisomatic targeting, in contrast to those from the CGE, which were dendrite targeting. Finally, inhibiting MGE interneurons in CA1 suppressed GDPs in CA3 and vice versa; conversely, they could also trigger GDPs in CA1 that propagated to CA3 and vice versa. Our data demonstrate a key role for MGE-derived interneurons in both generating and coordinating GDPs across the hippocampus.During nervous system development, immature circuits internally generate rhythmic patterns of electrical activity that promote the establishment of synaptic connections. Immature interneurons are excitatory rather than inhibitory and actively contribute to the generation of these spontaneous network events, referred to as giant depolarizing potentials (GDPs) in the hippocampus. Interneurons can be generally separated into two distinct groups based on their origin in the embryo from the medial or caudal ganglionic eminences (MGE and CGE). Here we show that MGE interneurons play a dominant role in generating GDPs compared with their CGE counterparts. They accomplish this due to their high synaptic connectivity within the local circuitry. Finally, they can control network activity across large regions of the developing hippocampus.

Pub.: 05 Mar '16, Pinned: 31 Aug '17

GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder.

Abstract: A core component to corticolimbic circuitry is the GABAergic interneuron. Neuroanatomic studies conducted over the past century have demonstrated several subtypes of interneuron defined by characteristic morphological appearances in Golgi-stained preparations. More recently, both cytochemical and electrophysiological techniques have defined various subtypes of GABA neuron according to synaptic connections, electrophysiological properties and neuropeptide content. These cells provide both inhibitory and disinhibitory modulation of cortical and hippocampal circuits and contribute to the generation of oscillatory rhythms, discriminative information processing and gating of sensory information within the corticolimbic system. All of these functions are abnormal in schizophrenia. Recent postmortem studies have provided consistent evidence that a defect of GABAergic neurotransmission probably plays a role in both schizophrenia and bipolar disorder. Many now believe that such a disturbance may be related to a perturbation of early development, one that may result in a disturbance of cell migration and the formation of normal lamination. The ingrowth of extrinsic afferents, such as the mesocortical dopamine projections, may "trigger" the appearance of a defective GABA system, particularly under stressful conditions when the modulation of the dopamine system is likely to be altered. Based on the regional and subregional distribution of changes in GABA cells in schizophrenia and bipolar disorder, it has been postulated that the basolateral nucleus of the amygdala may contribute to these abnormalities through an increased flow of excitatory activity. By using "partial" modeling, changes in the GABA system remarkably similar to those seen in schizophrenia and bipolar disorder have been induced in rat hippocampus. In the years to come, continued investigations of the GABA system in rodent, primate and human brain and the characterization of changes in specific phenotypic subclasses of interneurons in schizophrenia and bipolar disorder will undoubtedly provide important new insights into how the integration of this transmitter system may be altered in neuropsychiatric disease.

Pub.: 30 May '01, Pinned: 04 Aug '17

Expression of GABA and GABAA receptors by neurons of the subplate zone in developing primate occipital cortex: evidence for transient local circuits.

Abstract: Several lines of evidence suggest that the transient subplate zone of the embryonic mammalian telencephalon could influence cortical development through synaptic or trophic interactions with growing cortical afferents and migrating neurons. Since such interactions may involve neurotransmitters and their receptor molecules, we have examined the expression of GABA and subunits of the GABAA/benzodiazepine receptor complex in the occipital lobe of embryonic rhesus monkeys by immunochemistry and in situ hybridization. We found that during the second half of gestation, when the subplate zone reaches peak maturity in this species, many neurons can be immunolabeled with both GABA antisera and monoclonal antibodies against GABAA receptor subunits. The most robust labeling occurs at approximately embryonic day (E)125 (birth is at E165). Electron microscopic observations of receptor subunit-immunolabeled material confirmed that subunits of the GABAA receptor are localized in the subplate neurons and their dendritic processes. In many instances the reaction product is associated with the plasma membranes of labeled processes, some of which form symmetrical synapses with small unlabeled axon terminals. The results of in situ hybridization are in accord with the results of receptor subunit immunochemistry. From E80 to E141, hybridization signal for GABAA receptor subunit mRNA occurs in the subplate zone and increases steadily to peak levels between E125 and E141. The present results reveal that all the elements necessary for the formation of functional GABAergic synaptic circuitry are present in the subplate zone. Further, the ages showing the most pronounced receptor and transmitter expression in this primate coincide with the ingrowth of major cortical afferent systems. Taken together, these findings suggest that GABAergic local neuronal circuits in the subplate may be involved in the development of long tract connections stationed in this zone prior to their transfer to the overlying cortical plate.

Pub.: 01 Mar '92, Pinned: 14 Jul '17

Differential gene expression in migrating cortical interneurons during mouse forebrain development.

Abstract: Gamma-aminobutyric acid (GABA)ergic interneurons play a vital role in modulating the activity of the cerebral cortex, and disruptions to their function have been linked to neurological disorders such as schizophrenia and epilepsy. These cells originate in the ganglionic eminences (GE) of the ventral telencephalon and undergo tangential migration to enter the cortex. Currently, little is known about the signaling mechanisms that regulate interneuron migration. We therefore performed a microarray analysis comparing the changes in gene expression between the GABAergic interneurons that are actively migrating into the cortex with those in the GE. We were able to isolate pure populations of GABAergic cells by fluorescence-activated cell sorting of cortex and GE from embryonic brains of glutamate decarboxylase 67 (GAD67)-green fluorescent protein (GFP) transgenic mice. Our microarray analysis identified a number of novel genes that were upregulated in migrating cortical interneurons at both E13.5 and E15.5. Many of these genes have previously been shown to play a role in cell migration of both neuronal and non-neuronal cell types. In addition, several of the genes identified are involved in the regulation of migratory processes, such as neurite outgrowth, cell adhesion, and remodeling of the actin cytoskeleton and microtubule network. Moreover, quantitative polymerase chain reaction and in situ hybridization analyses confirmed that the expression of some of these genes is restricted to cortical interneurons. These data therefore provide a framework for future studies aimed at elucidating the complexities of interneuron migration and, in turn, may reveal important genes that are related to the development of specific neurological disorders.

Pub.: 13 Feb '10, Pinned: 14 Jul '17