Population Of GABAergic Neurons Research Articles

Expression of Gls and Gls2 glutaminase isoforms in astrocytes.

The expression of glutaminase in glial cells has been a controversial issue and matter of debate for many years. Actually, glutaminase is essentially considered as a neuronal marker in brain. Astrocytes are endowed with efficient and high capacity transport systems to recapture synaptic glutamate which seems to be consistent with the absence of glutaminase in these glial cells. In this work, a comprehensive study was devised to elucidate expression of glutaminase in neuroglia and, more concretely, in astrocytes. Immunocytochemistry in rat and human brain tissues employing isoform-specific antibodies revealed expression of both Gls and Gls2 glutaminase isozymes in glutamatergic and GABAergic neuronal populations as well as in astrocytes. Nevertheless, there was a different subcellular distribution: Gls isoform was always present in mitochondria while Gls2 appeared in two different locations, mitochondria and nucleus. Confocal microscopy and double immunofluorescence labeling in cultured astrocytes confirmed the same pattern previously seen in brain tissue samples. Astrocytic glutaminase expression was also assessed at the mRNA level, real-time quantitative RT-PCR detected transcripts of four glutaminase isozymes but with marked differences on their absolute copy number: the predominance of Gls isoforms over Gls2 transcripts was remarkable (ratio of 144:1). Finally, we proved that astrocytic glutaminase proteins possess enzymatic activity by in situ activity staining: concrete populations of astrocytes were labeled in the cortex, cerebellum and hippocampus of rat brain demonstrating functional catalytic activity. These results are relevant for the stoichiometry of the Glu/Gln cycle at the tripartite synapse and suggest novel functions for these classical metabolic enzymes.

Genetic ablation of VIAAT in glycinergic neurons causes a severe respiratory phenotype and perinatal death.

Both glycinergic and GABAergic neurons require the vesicular inhibitory amino acid transporter (VIAAT) for synaptic vesicle filling. Presynaptic GABA concentrations are determined by the GABA-synthesizing enzymes glutamate decarboxylase (GAD)65 and GAD67, whereas the presynaptic glycine content depends on the plasma membrane glycine transporter 2 (GlyT2). Although severely impaired, glycinergic transmission is not completely absent in GlyT2-knockout mice, suggesting that other routes of glycine uptake or de novo synthesis of glycine exist in presynaptic terminals. To investigate the consequences of a complete loss of glycinergic transmission, we generated a mouse line with a conditional ablation of VIAAT in glycinergic neurons by crossing mice with loxP-flanked VIAAT alleles with a GlyT2-Cre transgenic mouse line. Interestingly, conditional VIAAT knockout (VIAAT cKO) mice were not viable at birth. In addition to the dominant respiratory failure, VIAAT cKO showed an umbilical hernia and a cleft palate. Immunohistochemistry revealed an almost complete depletion of VIAAT in the brainstem. Electrophysiology revealed the absence of both spontaneous glycinergic and GABAergic inhibitory postsynaptic currents from hypoglossal motoneurons. Our results demonstrate that the deletion of VIAAT in GlyT2-Cre expressing neurons also strongly affects GABAergic transmission and suggest a large overlap of the glycinergic and the GABAergic neuron population during early development in the caudal parts of the brain.

La atorvastatina protege las neuronas GABAérgicas y dopaminérgicas del sistema nigroestriatal en un modelo experimental de isquemia cerebral focal transitoria en ratas

Introduction: Cerebral ischemia is the third leading cause of death and the primary cause of permanent disability worldwide. Atorvastatin is a promising drug with neuroprotective effects that may be useful for the treatment of stroke. However, the effects of atorvastatin on specific neuronal populations within the nigrostriatal system following cerebral ischemia are unknown. Objective: To evaluate the effects of atorvastatin on dopaminergic and GABAergic neuronal populations in exofocal brain regions in a model of transient occlusion of the middle cerebral artery. Materials and methods: Twenty-eight male eight-week-old Wistar rats were used in this study. Both sham and ischemic rats were treated with atorvastatin (10 mg/kg) or carboxymethylcellulose (placebo) by gavage at 6, 24, 48 and 72 hours post-reperfusion. We analyzed the immunoreactivity of glutamic acid decarboxylase and tyrosine hydroxylase in the globus pallidus, caudate putamen and substantia nigra. Results: We observed neurological damage and cell loss in the caudate putamen following ischemia. We also found an increase in tyrosine hydroxylase immunoreactivity in the medial globus pallidus and substantia nigra reticulata, as well as a decrease in glutamic acid decarboxylase immunoreactivity in the lateral globus pallidus in ischemic animals treated with a placebo. However, atorvastatin treatment was able to reverse these effects, significantly decreasing tyrosine hydroxylase levels in the medial globus pallidus and substantia nigra reticulata and significantly increasing glutamic acid decarboxylase levels in the lateral globus pallidus. Conclusion: Our data suggest that post-ischemia treatment with atorvastatin can have neuro-protective effects in exofocal regions far from the ischemic core by modulating the GABAergic and dopaminergic neuronal populations in the nigrostriatal system, which could be useful for preventing neurological disorders.

Atorvastatin protects GABAergic and dopaminergic neurons in the nigrostriatal system in an experimental rat model of transient focal cerebral ischemia.

Cerebral ischemia is the third leading cause of death and the primary cause of permanent disability worldwide. Atorvastatin is a promising drug with neuroprotective effects that may be useful for the treatment of stroke. However, the effects of atorvastatin on specific neuronal populations within the nigrostriatal system following cerebral ischemia are unknown. To evaluate the effects of atorvastatin on dopaminergic and GABAergic neuronal populations in exofocal brain regions in a model of transient occlusion of the middle cerebral artery. Twenty-eight male eight-week-old Wistar rats were used in this study. Both sham and ischemic rats were treated with atorvastatin (10 mg/kg) or carboxymethylcellulose (placebo) by gavage at 6, 24, 48 and 72 hours post-reperfusion. We analyzed the immunoreactivity of glutamic acid decarboxylase and tyrosine hydroxylase in the globus pallidus, caudate putamen and substantia nigra. We observed neurological damage and cell loss in the caudate putamen following ischemia. We also found an increase in tyrosine hydroxylase immunoreactivity in the medial globus pallidus and substantia nigra reticulata, as well as a decrease in glutamic acid decarboxylase immunoreactivity in the lateral globus pallidus in ischemic animals treated with a placebo. However, atorvastatin treatment was able to reverse these effects, significantly decreasing tyrosine hydroxylase levels in the medial globus pallidus and substantia nigra reticulata and significantly increasing glutamic acid decarboxylase levels in the lateral globus pallidus. Our data suggest that post-ischemia treatment with atorvastatin can have neuro-protective effects in exofocal regions far from the ischemic core by modulating the GABAergic and dopaminergic neuronal populations in the nigrostriatal system, which could be useful for preventing neurological disorders.

Transplantation of GABAergic Cells Derived from Bioreactor-Expanded Human Neural Precursor Cells Restores Motor and Cognitive Behavioral Deficits in a Rodent Model of Huntington's Disease

Huntington's disease (HD) is a neurodegenerative disorder that is characterized by progressive dementia, choreiform involuntary movements, and emotional deterioration. Neuropathological features include the progressive degeneration of striatal γ-aminobutyric acid (GABA) neurons. New therapeutic approaches, such as the transplantation of human neural precursor cells (hNPCs) to replace damaged or degenerated cells, are currently being investigated. The aim of this study was to investigate the potential for utilizing telencephalic hNPCs expanded in suspension bioreactors for cell restorative therapy in a rodent model of HD. hNPCs were expanded in a hydrodynamically controlled and homogeneous environment under serum-free conditions. In vitro analysis revealed that the bioreactor-expanded telencephalic (BET)-hNPCs could be differentiated into a highly enriched population of GABAergic neurons. Behavioral assessments of unilateral striatal quinolinic acid-lesioned rodents revealed a significant improvement in motor and memory deficits following transplantation with GABAergic cells differentiated from BET-hNPCs. Immunohistochemical analysis revealed that transplanted BET-hNPCs retained a GABAergic neuronal phenotype without aberrant transdifferentiation or tumor formation, indicating that BET-hNPCs are a safe source of cells for transplantation. This preclinical study has important implications as the transplantation of GABAergic cells derived from predifferentiated BET-hNPCs may be a safe and feasible cell replacement strategy to promote behavioral recovery in HD.

Two specific populations of GABAergic neurons originating from the medial and the caudal ganglionic eminences aid in proper navigation of callosal axons

The corpus callosum (CC) plays a crucial role in interhemispheric communication. It has been shown that CC formation relies on the guidepost cells located in the midline region that include glutamatergic and GABAergic neurons as well as glial cells. However, the origin of these guidepost GABAergic neurons and their precise function in callosal axon pathfinding remain to be investigated. Here, we show that two distinct GABAergic neuronal subpopulations converge toward the midline prior to the arrival of callosal axons. Using in vivo and ex vivo fate mapping we show that CC GABAergic neurons originate in the caudal and medial ganglionic eminences (CGE and MGE) but not in the lateral ganglionic eminence (LGE). Time lapse imaging on organotypic slices and in vivo analyses further revealed that CC GABAergic neurons contribute to the normal navigation of callosal axons. The use of Nkx2.1 knockout (KO) mice confirmed a role of these neurons in the maintenance of proper behavior of callosal axons while growing through the CC. Indeed, using in vitro transplantation assays, we demonstrated that both MGE- and CGE-derived GABAergic neurons exert an attractive activity on callosal axons. Furthermore, by combining a sensitive RT-PCR technique with in situ hybridization, we demonstrate that CC neurons express multiple short and long range guidance cues. This study strongly suggests that MGE- and CGE-derived interneurons may guide CC axons by multiple guidance mechanisms and signaling pathways.

Nicotine induction of theta frequency oscillations in rodent medial septal diagonal band in vitro

This study aimed to examine the role of the nicotinic receptor (nAChR) in the generation of theta oscillations (4-12 Hz) in vitro. Electrophysiological studies were performed on medial septal diagonal band area (MSDB) slices to measure theta oscillation. Immunofluorescence and confocal microscopy studies were carried out to detect α4 nAChR and β2 nAChR subunits in perfused-fixed tissue from VGluT2-GFP and GAD67-GFP transgenic mice. Application of nicotine to MSDB slices produced persistent theta oscillations in which area power increased in a dose-responsive manner. This activity was inhibited by GABAA receptor antagonists and partially by ionotropic glutamate receptor antagonists, indicating the involvement of local GABAergic and glutamatergic neurons in the production of the rhythmic activity. The nicotine-induced theta activity was also inhibited selectively by non-α7*nAChR antagonists, suggesting the presence of these receptor types on GABAergic and glutamatergic neuron populations in the MSDB. This was confirmed by immunofluorescence and confocal microscopy studies in transgenic mice in which the GABAergic and glutamatergic neurons express green fluorescent protein (GFP), showing localisation of β2 nAChR and α4 nAChR subunits, the most common constituents of non-α7*nAChRs, in both cell types in the MSDB. Theta activity in the MSDB may be generated by tonic stimulation of non-α7*nAChRs.

810 – Zolpidem-induced galactorrhea via gabaergic inhibition of dopamine: a case report

Objective To discuss a case of zolpidem-induced galactorrhea. Introduction The prevalence of insomnia can be as high as 32 to 33%. Non-benzodiazepines (such as zolpidem) have become more commonly used to treat insomnia. Case report The patient is a 29-year-old woman with a history of (PTSD) who presented with PTSD associated insomnia. She was started on zolpidem 5 mg po qhs. Two months after the initiation of zolpidem treatment, the patient presented with breast tenderness and galactorrhea. Zolpidem was discontinued and the galactorrhea resolved after two weeks. A serum prolactin level drawn shortly after discontinuation of zolpidem was 15.67 mg/ml. Discussion Zolpidem has a high affinity at the α1 containing GABAA receptors, with reduced affinity for those containing the α2- and α3- GABAA receptor subunits and minimal affinity for α5 receptor subunit. Psychotropic drugs have been well recognized to produce hyperprolactinemia. However, there has been no reported case of zolpidem-induced hyperprolactinemia. Specifically, zolpidem has been noted to activate GABAergic neurons within the ventral tegmental area (VTA), where there is a sizable population of GABAergic neurons. These GABAergic neurons regulate the firing of dopaminergic counterparts, also located in the VTA, which send projections throughout the brain. This inhibition results in a decrease in the dopaminergic inhibitory influence on prolactin and an increase in prolactin releasing factors which act on the anterior pituitary, leading to hyperprolactinemia and thus galactorrhea. Conclusion Pharmacologically induced hyperprolactinemia may be a problem of underestimated prevalence due to the lack of externally visible symptoms.

The role of nitric oxide in pre-synaptic plasticity and homeostasis.

Since the observation that nitric oxide (NO) can act as an intercellular messenger in the brain, the past 25 years have witnessed the steady accumulation of evidence that it acts pre-synaptically at both glutamatergic and GABAergic synapses to alter release-probability in synaptic plasticity. NO does so by acting on the synaptic machinery involved in transmitter release and, in a coordinated fashion, on vesicular recycling mechanisms. In this review, we examine the body of evidence for NO acting as a retrograde factor at synapses, and the evidence from in vivo and in vitro studies that specifically establish NOS1 (neuronal nitric oxide synthase) as the important isoform of NO synthase in this process. The NOS1 isoform is found at two very different locations and at two different spatial scales both in the cortex and hippocampus. On the one hand it is located diffusely in the cytoplasm of a small population of GABAergic neurons and on the other hand the alpha isoform is located discretely at the post-synaptic density (PSD) in spines of pyramidal cells. The present evidence is that the number of NOS1 molecules that exist at the PSD are so low that a spine can only give rise to modest concentrations of NO and therefore only exert a very local action. The NO receptor guanylate cyclase is located both pre- and post-synaptically and this suggests a role for NO in the coordination of local pre- and post-synaptic function during plasticity at individual synapses. Recent evidence shows that NOS1 is also located post-synaptic to GABAergic synapses and plays a pre-synaptic role in GABAergic plasticity as well as glutamatergic plasticity. Studies on the function of NO in plasticity at the cellular level are corroborated by evidence that NO is also involved in experience-dependent plasticity in the cerebral cortex.

SINs and SOMs: neural microcircuits for size tuning in the zebrafish and mouse visual pathway

In many animals, a fast and reliable circuit for discriminating between predator-sized objects and edible (prey-sized) objects is necessary for survival. How are receptive fields (RFs) in visual brain areas organized to extract information about size? Recent studies from the zebrafish optic tectum and the mouse visual cortex suggest de novo shaping of RFs by subtypes of inhibitory neurons. Del Bene et al. (2010) describe a population of GABAergic neurons in the zebrafish optic tectum (superficial interneurons, SINs) that are necessary for size filtering during prey capture. Adesnik et al. (2012) describe a somatostatin-expressing interneuron population (SOMs) that confers surround suppression on layer II/III pyramidal cells in mouse V1. Strikingly both the SINs and the SOMs, display size-dependent response properties. Increasing visual stimulus size increases excitatory input to these neurons. Dampening SIN or SOM activity alters tuning of neighboring circuits such that they lose preference for small objects. Both results provide exciting evidence for mechanisms of size filtering in visual circuits. Here we review the roles of the SINs and the SOMs and speculate on the similarity of such spatial filters across species.

The transcription factor Uncx4.1 acts in a short window of midbrain dopaminergic neuron differentiation

BackgroundThe homeobox containing transcription factor Uncx4.1 is, amongst others, expressed in the mouse midbrain. The early expression of this transcription factor in the mouse, as well as in the chick midbrain, points to a conserved function of Uncx4.1, but so far a functional analysis in this brain territory is missing. The goal of the current study was to analyze in which midbrain neuronal subgroups Uncx4.1 is expressed and to examine whether this factor plays a role in the early development of these neuronal subgroups.ResultsWe have shown that Uncx4.1 is expressed in GABAergic, glutamatergic and dopaminergic neurons in the mouse midbrain. In midbrain dopaminergic (mDA) neurons Uncx4.1 expression is particularly high around E11.5 and strongly diminished already at E17.5. The analysis of knockout mice revealed that the loss of Uncx4.1 is accompanied with a 25% decrease in the population of mDA neurons, as marked by tyrosine hydroxylase (TH), dopamine transporter (DAT), Pitx3 and Ngn2. In contrast, the number of glutamatergic Pax6-positive cells was augmented, while the GABAergic neuron population appears not affected in Uncx4.1-deficient embryos.ConclusionWe conclude that Uncx4.1 is implicated in the development of mDA neurons where it displays a unique temporal expression profile in the early postmitotic stage. Our data indicate that the mechanism underlying the role of Uncx4.1 in mDA development is likely related to differentiation processes in postmitotic stages, and where Ngn2 is engaged. Moreover, Uncx4.1 might play an important role during glutamatergic neuronal differentiation in the mouse midbrain.

Differential firing pattern and response to lighting conditions of rat intergeniculate leaflet neurons projecting to suprachiasmatic nucleus or contralateral intergeniculate leaflet

The intergeniculate leaflet (IGL) of the lateral geniculate body in the rat is a population of GABAergic neurons that can be divided into two, anatomically and neurochemically distinct populations. One population comprises neuropeptide-Y (NPY)-positive neurons that form the geniculohypothalamic tract innervating the suprachiasmatic nuclei (SCN) and the other population comprises enkephalin-positive (ENK) neurons giving rise to the geniculo-geniculate tract innervating the contralateral IGL (cIGL). Previous electrophysiological studies have observed various patterns of firing and different responses to changes in lighting conditions of IGL neurons in vitro and in vivo. The aim of the present study was to determine if these distinct properties could be ascribed to differentially projecting IGL neurons. Neuron activity was recorded extracellularly in the IGL of anaesthetised rats under different lighting conditions (i.e. light/dark). Antidromic activation was used to identify recorded cells as projecting to the SCN or the contralateral IGL. All IGL neurons identified as projecting to the contralateral IGL displayed infra-slow oscillatory activity (ISO; i.e. slow rhythmic bursts of action potentials). ISO of these neurons was sustained in the light and was diminished in the darkness. In contrast, all IGL neurons identified as projecting to the SCN displayed a low level of firing in the light and a majority of these cells increased firing in the darkness. All IGL neurons projecting to the SCN were characterised by an irregular pattern of firing in the light and dark. These data are the first to demonstrate that differentially projecting rat intergeniculate leaflet neurons are characterised by distinct firing patterns and opposite responses to light and dark conditions.

GABA concentration and GABAergic neuron populations in limbic areas are differentially altered by brain serotonin deficiency in Tph2 knockout mice

While tryptophan hydroxylase-2 (Tph2) null mutant (Tph2(-/-)) mice are completely deficient in brain serotonin (5-HT) synthesis, the formation of serotonergic neurons and pathfinding of their projections are not impaired. However, 5-HT deficiency, during development and in the adult, might affect morphological and functional parameters of other neural systems. To assess the influence of 5-HT deficiency on γ-amino butyric acid (GABA) systems, we carried out measurements of GABA concentrations in limbic brain regions of adult male wildtype (wt), heterozygous (Tph2(+/-)) and Tph2(-/-) mice. In addition, unbiased stereological estimation of GABAergic interneuron numbers and density was performed in subregions of amygdala and hippocampus. Amygdala and prefrontal cortex displayed significantly increased and decreased GABA concentrations, respectively, exclusively in Tph2(+/-) mice while no changes were detected between Tph2(-/-) and wt mice. In contrast, in the hippocampus, increased GABA concentrations were found in Tph2(-/-) mice. While total cell density in the anterior basolateral amygdala did not differ between genotypes, the number and density of the GABAergic interneurons were significantly decreased in Tph2(-/-) mice, with the group of parvalbumin (PV)-immunoreactive (ir) interneurons contributing somewhat less to the decrease than that of non-PV-ir GABAergic interneurons. Major morphological changes were also absent in the dorsal hippocampus, and only a trend toward reduced density of PV-ir cells was observed in the CA3 region of Tph2(-/-) mice. Our findings are the first to document that life-long reduction or complete lack of brain 5-HT transmission causes differential changes of GABA systems in limbic regions which are key players in emotional learning and memory processes. The changes likely reflect a combination of developmental alterations and functional adaptations of emotion circuits to balance the lack of 5-HT, and may underlie altered emotional behavior in 5-HT-deficient mice. Taken together, our findings provide further insight into the mechanisms how life-long 5-HT deficiency impacts the pathogenesis of anxiety- and fear-related disorders.

Transcriptional regulatory mechanisms underlying the GABAergic neuron fate in different diencephalic prosomeres

Diverse mechanisms regulate development of GABAergic neurons in different regions of the central nervous system. We have addressed the roles of a proneural gene, Ascl1, and a postmitotic selector gene, Gata2, in the differentiation of GABAergic neuron subpopulations in three diencephalic prosomeres: prethalamus (P3), thalamus (P2) and pretectum (P1). Although the different proliferative progenitor populations of GABAergic neurons commonly express Ascl1, they have distinct requirements for it in promotion of cell-cycle exit and GABAergic neuron identity. Subsequently, Gata2 is activated as postmitotic GABAergic precursors are born. In P1, Gata2 regulates the neurotransmitter identity by promoting GABAergic and inhibiting glutamatergic neuron differentiation. Interestingly, Gata2 defines instead the subtype of GABAergic neurons in the rostral thalamus (pTh-R), which is a subpopulation of P2. Without Gata2, the GABAergic precursors born in the pTh-R fail to activate subtype-specific markers, but start to express genes typical of GABAergic precursors in the neighbouring P3 domain. Thus, our results demonstrate diverse mechanisms regulating differentiation of GABAergic neuron subpopulations and suggest a role for Gata2 as a selector gene of both GABAergic neuron neurotransmitter and prosomere subtype identities in the developing diencephalon. Our results demonstrate for the first time that neuronal identities between distinct prosomeres can still be transformed in postmitotic neuronal precursors.

Drosophila Cytokine Unpaired 2 Regulates Physiological Homeostasis by Remotely Controlling Insulin Secretion

In Drosophila, the fat body (FB), a functional analog of the vertebrate adipose tissue, is the nutrient sensor that conveys the nutrient status to the insulin-producing cells (IPCs) in the fly brain to release Drosophila insulin-like peptides (Dilps). Dilp secretion in turn regulates energy balance and promotes systemic growth. We identify Unpaired 2 (Upd2), a protein with similarities to type I cytokines, as a secreted factor produced by the FB in the fed state. When upd2 function is perturbed specifically in the FB, it results in a systemic reduction in growth and alters energy metabolism. Upd2 activates JAK/STAT signaling in a population of GABAergic neurons that project onto the IPCs. This activation relieves the inhibitory tone of the GABAergic neurons on the IPCs, resulting in the secretion of Dilps. Strikingly, we find that human Leptin can rescue the upd2 mutant phenotypes, suggesting that Upd2 is the functional homolog of Leptin.

Out with the old (model)

The external globus pallidus contains two populations of interconnected GABAergic neurons, one of which exclusively targets the striatum.

Dichotomous Organization of the External Globus Pallidus

SummaryDifferent striatal projection neurons are the origin of a dual organization essential for basal ganglia function. We have defined an analogous division of labor in the external globus pallidus (GPe) of Parkinsonian rats, showing that the distinct temporal activities of two populations of GPe neuron in vivo are underpinned by distinct molecular profiles and axonal connectivities. A first population of prototypic GABAergic GPe neurons fire antiphase to subthalamic nucleus (STN) neurons, often express parvalbumin, and target downstream basal ganglia nuclei, including STN. In contrast, a second population (arkypallidal neurons) fire in-phase with STN neurons, express preproenkephalin, and only innervate the striatum. This novel cell type provides the largest extrinsic GABAergic innervation of striatum, targeting both projection neurons and interneurons. We conclude that GPe exhibits several core components of a dichotomous organization as fundamental as that in striatum. Thus, two populations of GPe neuron together orchestrate activities across all basal ganglia nuclei in a cell-type-specific manner.

Synaptic and Intrinsic Activation of GABAergic Neurons in the Cardiorespiratory Brainstem Network

GABAergic pathways in the brainstem play an essential role in respiratory rhythmogenesis and interactions between the respiratory and cardiovascular neuronal control networks. However, little is known about the identity and function of these GABAergic inhibitory neurons and what determines their activity. In this study we have identified a population of GABAergic neurons in the ventrolateral medulla that receive increased excitatory post-synaptic potentials during inspiration, but also have spontaneous firing in the absence of synaptic input. Using transgenic mice that express GFP under the control of the Gad1 (GAD67) gene promoter, we determined that this population of GABAergic neurons is in close apposition to cardioinhibitory parasympathetic cardiac neurons in the nucleus ambiguus (NA). These neurons fire in synchronization with inspiratory activity. Although they receive excitatory glutamatergic synaptic inputs during inspiration, this excitatory neurotransmission was not altered by blocking nicotinic receptors, and many of these GABAergic neurons continue to fire after synaptic blockade. The spontaneous firing in these GABAergic neurons was not altered by the voltage-gated calcium channel blocker cadmium chloride that blocks both neurotransmission to these neurons and voltage-gated Ca2+ currents, but spontaneous firing was diminished by riluzole, demonstrating a role of persistent sodium channels in the spontaneous firing in these cardiorespiratory GABAergic neurons that possess a pacemaker phenotype. The spontaneously firing GABAergic neurons identified in this study that increase their activity during inspiration would support respiratory rhythm generation if they acted primarily to inhibit post-inspiratory neurons and thereby release inspiration neurons to increase their activity. This population of inspiratory-modulated GABAergic neurons could also play a role in inhibiting neurons that are most active during expiration and provide a framework for respiratory sinus arrhythmia as there is an increase in heart rate during inspiration that occurs via inhibition of premotor parasympathetic cardioinhibitory neurons in the NA during inspiration.

Les progrès sur l’architecture du sommeil paradoxal depuis William Dement et Michel Jouvet

Paradoxical or REM sleep, characterized by cortical activation combined with muscle atonia and rapid eye movements, was discovered at the end of the 1950s by Michel Jouvet and William C. Dement. Studies over the next twenty years suggested that the onset and maintenance of paradoxical sleep was due to a reciprocal inhibitory interaction between monoaminergic neurons inhibiting PS and cholinergic neurons generating PS located in a small part of the pontine reticular formation called the sublaterodorsal tegmental nucleus. Our recent studies rather indicate that these neurons are respectively GABAergic and glutamatergic. Further, they suggest that three populations of GABAergic neurons and population of hypothalamic neurons expressing melanin concentrating hormone, a peptide, play a important role in PS control.

High-Throughput Analysis of Promoter Occupancy Reveals New Targets for Arx, a Gene Mutated in Mental Retardation and Interneuronopathies

Genetic investigations of X-linked intellectual disabilities have implicated the ARX (Aristaless-related homeobox) gene in a wide spectrum of disorders extending from phenotypes characterised by severe neuronal migration defects such as lissencephaly, to mild or moderate forms of mental retardation without apparent brain abnormalities but with associated features of dystonia and epilepsy. Analysis of Arx spatio-temporal localisation profile in mouse revealed expression in telencephalic structures, mainly restricted to populations of GABAergic neurons at all stages of development. Furthermore, studies of the effects of ARX loss of function in humans and animal models revealed varying defects, suggesting multiple roles of this gene during brain development. However, to date, little is known about how ARX functions as a transcription factor and the nature of its targets. To better understand its role, we combined chromatin immunoprecipitation and mRNA expression with microarray analysis and identified a total of 1006 gene promoters bound by Arx in transfected neuroblastoma (N2a) cells and in mouse embryonic brain. Approximately 24% of Arx-bound genes were found to show expression changes following Arx overexpression or knock-down. Several of the Arx target genes we identified are known to be important for a variety of functions in brain development and some of them suggest new functions for Arx. Overall, these results identified multiple new candidate targets for Arx and should help to better understand the pathophysiological mechanisms of intellectual disability and epilepsy associated with ARX mutations.