Showing papers on "GABAergic published in 2009"
TL;DR: Over 95% of all PPTg/LDTg cholinergic neurons lack transcripts encoding either vGluT2 mRNA or GAD mRNA, which means co‐release of acetylcholine with either glutamate or GABA is unlikely to be a major factor in the interactions between acetyl choline, glutamate and GABA at the postsynaptic site.
Abstract: The pedunculopontine tegmental nucleus (PPTg) and laterodorsal tegmental nucleus (LDTg) provide cholinergic afferents to several brain areas. This cholinergic complex has been suggested to play a role in sleep, waking, motor function, learning and reward. To have a better understanding of the neurochemical organization of the PPTg/LDTg we characterized the phenotype of PPTg/LDTg neurons by determining in these cells the expression of transcripts encoding choline acetyltransferase (ChAT), glutamic acid decarboxylase (GAD) or the vesicular glutamate transporters (vGluT1, vGluT2 and vGluT3). Within the PPTg/LDTg complex we found neurons expressing ChAT, vGluT2 or GAD transcripts, these neuronal phenotypes were intermingled, but not homogeneously distributed within the PPTg or LDTg. Previous studies suggested the presence of either glutamate or gamma-aminobutyric acid (GABA) immunolabeling in a large number of PPTg/LDTg cholinergic neurons, leading to the widespread notion that PPTg/LDTg cholinergic neurons co-release acetylcholine together with either glutamate or GABA. To assess the glutamatergic or GABAergic nature of the PPTg/LDTg cholinergic neurons, we combined in situ hybridization (to detect vGluT2 or GAD transcripts) and immunohistochemistry (to detect ChAT), and found that over 95% of all PPTg/LDTg cholinergic neurons lack transcripts encoding either vGluT2 mRNA or GAD mRNA. As the vast majority of PPTg/LDTg cholinergic neurons lack transcripts encoding essential proteins for the vesicular transport of glutamate or for the synthesis of GABA, co-release of acetylcholine with either glutamate or GABA is unlikely to be a major factor in the interactions between acetylcholine, glutamate and GABA at the postsynaptic site.
435 citations
TL;DR: The elucidation of the mechanisms that underlie adaptations to ethanol exposure are leading to a better understanding of the regulation of inhibitory transmission and new targets for therapies to support recovery from ethanol withdrawal and alcoholism.
Abstract: The past decade has brought many advances in our understanding of GABAA receptor-mediated ethanol action in the central nervous system. We now know that specific GABAA receptor subtypes are sensitive to ethanol at doses attained during social drinking while other subtypes respond to ethanol at doses attained by severe intoxication. Furthermore, ethanol increases GABAergic neurotransmission through indirect effects, including the elevation of endogenous GABAergic neuroactive steroids, presynaptic release of GABA, and dephosphorylation of GABAA receptors promoting increases in GABA sensitivity. Ethanol’s effects on intracellular signaling also influence GABAergic transmission in multiple ways that vary across brain regions and cell types. The effects of chronic ethanol administration are influenced by adaptations in GABAA receptor function, expression, trafficking, and subcellular localization that contribute to ethanol tolerance, dependence, and withdrawal hyperexcitability. Adolescents exhibit altered sensitivity to ethanol actions, the tendency for higher drinking and longer lasting GABAergic adaptations to chronic ethanol administration. The elucidation of the mechanisms that underlie adaptations to ethanol exposure are leading to a better understanding of the regulation of inhibitory transmission and new targets for therapies to support recovery from ethanol withdrawal and alcoholism.
411 citations
TL;DR: It is suggested that activation of the PBN by AgRP neuron ablation or gastrointestinal malaise inhibits feeding, and chronic delivery of bretazenil during loss of AgRP neurons provides time to establish compensatory mechanisms that eventually allow mice to eat.
403 citations
TL;DR: It is demonstrated that GABAA receptors are reduced in three brain regions that have previously been implicated in the pathogenesis of autism, suggesting widespread GABAergic dysfunction in the brains of subjects with autism.
Abstract: Gamma-aminobutyric acid A (GABAA) receptors are ligand-gated ion channels responsible for mediation of fast inhibitory action of GABA in the brain Preliminary reports have demonstrated altered expression of GABA receptors in the brains of subjects with autism suggesting GABA/glutamate system dysregulation We investigated the expression of four GABAA receptor subunits and observed significant reductions in GABRA1, GABRA2, GABRA3, and GABRB3 in parietal cortex (Brodmann’s Area 40 (BA40)), while GABRA1 and GABRB3 were significantly altered in cerebellum, and GABRA1 was significantly altered in superior frontal cortex (BA9) The presence of seizure disorder did not have a significant impact on GABAA receptor subunit expression in the three brain areas Our results demonstrate that GABAA receptors are reduced in three brain regions that have previously been implicated in the pathogenesis of autism, suggesting widespread GABAergic dysfunction in the brains of subjects with autism
395 citations
TL;DR: The results suggest that noncoding RNA-dependent balanced gene regulation in embryonic brain is critical for proper formation of GABA-dependent neuronal circuitry in adult brain.
Abstract: Genomic studies demonstrate that, although the majority of the mammalian genome is transcribed, only about 2% of these transcripts are code for proteins. We investigated how the long, polyadenylated Evf2 noncoding RNA regulates transcription of the homeodomain transcription factors DLX5 and DLX6 in the developing mouse forebrain. We found that, in developing ventral forebrain, Evf2 recruited DLX and MECP2 transcription factors to important DNA regulatory elements in the Dlx5/6 intergenic region and controlled Dlx5, Dlx6 and Gad1 expression through trans and cis-acting mechanisms. Evf2 mouse mutants had reduced numbers of GABAergic interneurons in early postnatal hippocampus and dentate gyrus. Although the numbers of GABAergic interneurons and Gad1 RNA levels returned to normal in Evf2 mutant adult hippocampus, reduced synaptic inhibition occurred. These results suggest that noncoding RNA-dependent balanced gene regulation in embryonic brain is critical for proper formation of GABA-dependent neuronal circuitry in adult brain.
350 citations
TL;DR: This study investigated brain regions that are known to be implicated in the neurobiology of suicide and major depression are likely to represent valid global molecular alterations and suggests a global brain alteration of GLU and GABA receptor subunit genes in these conditions.
Abstract: BackgroundMost studies investigating the neurobiology of depression and suicide have focused on the serotonergic system. While it seems clear that serotonergic alterations play a role in the pathogenesis of these major public health problems, dysfunction in additional neurotransmitter systems and other molecular alterations may also be implicated. Microarray expression studies are excellent screening tools to generate hypotheses about additional molecular processes that may be at play. In this study we investigated brain regions that are known to be implicated in the neurobiology of suicide and major depression are likely to represent valid global molecular alterations.Methodology/Principal FindingsWe performed gene expression analysis using the HG-U133AB chipset in 17 cortical and subcortical brain regions from suicides with and without major depression and controls. Total mRNA for microarray analysis was obtained from 663 brain samples isolated from 39 male subjects, including 26 suicide cases and 13 controls diagnosed by means of psychological autopsies. Independent brain samples from 34 subjects and animal studies were used to control for the potential confounding effects of comorbidity with alcohol. Using a Gene Ontology analysis as our starting point, we identified molecular pathways that may be involved in depression and suicide, and performed follow-up analyses on these possible targets. Methodology included gene expression measures from microarrays, Gene Score Resampling for global ontological profiling, and semi-quantitative RT-PCR. We observed the highest number of suicide specific alterations in prefrontal cortical areas and hippocampus. Our results revealed alterations of synaptic neurotransmission and intracellular signaling. Among these, Glutamatergic (GLU) and GABAergic related genes were globally altered. Semi-quantitative RT-PCR results investigating expression of GLU and GABA receptor subunit genes were consistent with microarray data.Conclusions/SignificanceThe observed results represent the first overview of global expression changes in brains of suicide victims with and without major depression and suggest a global brain alteration of GLU and GABA receptor subunit genes in these conditions.
347 citations
TL;DR: It is shown that individual performance on a visual orientation discrimination task is correlated with both the resting concentration of GABA and the frequency of stimulus-induced gamma oscillations in human visual cortex, and a key role is suggested for GABAergic gamma oscillation frequency in visual discrimination tasks.
Abstract: Neuronal orientation selectivity has been shown in animal models to require corticocortical network cooperation and to be dependent on the presence of GABAergic inhibition. However, it is not known whether variability in these fundamental neurophysiological parameters leads to variability in behavioral performance. Here, using a combination of magnetic resonance spectroscopy, magnetoencephalography, and visual psychophysics, we show that individual performance on a visual orientation discrimination task is correlated with both the resting concentration of GABA and the frequency of stimulus-induced gamma oscillations in human visual cortex. Behaviorally, a strong oblique effect was found, with the mean angular threshold for oblique discrimination being five times higher than that for vertically oriented stimuli. Similarly, we found an oblique effect for the dependency of performance on neurophysiological parameters. Orientation detection thresholds were significantly negatively correlated with visual cortex GABA concentration for obliquely oriented patterns (r = −0.65, p < 0.015) but did not reach significance for vertically oriented stimuli (r = −0.39, p = 0.2). Similarly, thresholds for obliquely oriented stimuli were negatively correlated with gamma oscillation frequency (r = −0.65, p < 0.017), but thresholds for vertical orientations were not (r = −0.02, p = 0.9). Gamma oscillation frequency was positively correlated with GABA concentration in primary visual cortex (r = 0.67, p < 0.013). These results confirm the importance of GABAergic inhibition in orientation selectivity and demonstrate, for the first time, that interindividual performance on a simple visual task is linked to neurotransmitter concentration. The results also suggest a key role for GABAergic gamma oscillations in visual discrimination tasks.
328 citations
TL;DR: Results indicate that GABA(A)R diffusion dynamics are directly linked to rapid and plastic modifications of inhibitory synaptic transmission in response to changes in intracellular Ca(2+) concentration, which would favor the onset of LTP during conditioning.
270 citations
TL;DR: In this paper, the authors used magnetic resonance spectroscopy to define mechanisms mediating this inhibition by noninvasively measuring local changes in the cortical concentrations of γ-aminobutyric acid (GABA) and glutamate/glutamine (Glx).
Abstract: Continuous theta burst stimulation (cTBS) is a novel transcranial stimulation technique that causes significant inhibition of synaptic transmission for ≤1 h when applied over the primary motor cortex (M1) in humans. Here we use magnetic resonance spectroscopy to define mechanisms mediating this inhibition by noninvasively measuring local changes in the cortical concentrations of γ-aminobutyric acid (GABA) and glutamate/glutamine (Glx). cTBS to the left M1 led to an increase in GABA compared with stimulation at a control site without significant change in Glx. This direct evidence for increased GABAergic interneuronal activity is framed in terms of a new hypothesis regarding mechanisms underlying cTBS.
269 citations
TL;DR: It is shown that another subpallial structure, the preoptic area, is a novel source of cortical GABAergic interneurons in the mouse, and in utero labeling and genetic lineage-tracing experiments demonstrate that neurons born in this region migrate to the neocortex and hippocampus, where they differentiate into a distinct population of GABAergicInterneuron with relatively uniform neurochemical, morphological, and electrophysiological properties.
Abstract: GABA-containing (GABAergic) interneurons play an important role in the function of the cerebral cortex. Through mostly inhibitory mechanisms, interneurons control hyperexcitability and synchronize and shape the spatiotemporal dynamics of cortical activity underlying various brain functions. Studies over the past 10 years have demonstrated that, in most mammals, interneurons originate during development from the subcortical telencephalon--the subpallium--and reach the cerebral cortex through tangential migration. Until now, interneurons have been demonstrated to derive exclusively from two subpallial regions, the medial ganglionic eminence and the caudal ganglionic eminence. Here, we show that another subpallial structure, the preoptic area, is a novel source of cortical GABAergic interneurons in the mouse. In utero labeling and genetic lineage-tracing experiments demonstrate that neurons born in this region migrate to the neocortex and hippocampus, where they differentiate into a distinct population of GABAergic interneurons with relatively uniform neurochemical, morphological, and electrophysiological properties.
261 citations
TL;DR: It is found that rat hippocampal interneurons hyperpolarized pyramidal cells irrespective of the location of their synapses along the somato-dendritic axis.
Abstract: Although GABAergic interneurons are the main source of synaptic inhibition in the cortex, activation of GABA(A) receptors has been shown to depolarize specific neuronal compartments, resulting in excitation. By using a noninvasive approach to monitor the effect of individual interneurons on the pyramidal cell population, we found that rat hippocampal interneurons hyperpolarized pyramidal cells irrespective of the location of their synapses along the somato-dendritic axis.
TL;DR: The identification of a proximate mediator of HPA-inhibitory limbic influences provides a framework for clarifying how inhibitory neural and hormonal controls of H PA output are integrated, adaptations of the axis to chronic stress are effected, and how endocrine abnormalities may contribute to stress-related psychiatric illnesses in which mPFC dysfunction is implicated.
Abstract: Complementing its roles in cognitive and affective information processing, the medial prefrontal cortex (mPFC) is a nodal point of a limbic forebrain circuit that modulates stress-related homeostatic mechanisms, including the hypothalamic-pituitary-adrenal (HPA) axis. mPFC influences on HPA output are predominantly inhibitory and emanate from the prelimbic and/or dorsal anterior cingulate cortical fields (PL and ACd, respectively). mPFC projections do not target HPA effector neurons in the paraventricular hypothalamic nucleus (PVH) directly, distributing instead to nearby forebrain regions, including some that house GABAergic neurons implicated in inhibitory PVH control. To identify pathway(s) subserving HPA-inhibitory mPFC influences, an initial screen for sources of GABAergic input to PVH whose sensitivity to an acute emotional (restraint) stress was diminished by PL/ACd lesions identified a discrete region of the anterior bed nucleus of the stria terminalis (aBST) as a candidate for fulfilling this role. Anatomical tracing experiments confirmed projections from PL (but not ACd) to implicated aBST cell groups, and from these to PVH. Finally, selective immunotoxin-mediated ablation of GABAergic aBST neurons recapitulated the effects of PL/ACd lesions on acute stress-induced activation of HPA output. The identification of a proximate mediator of HPA-inhibitory limbic influences provides a framework for clarifying how inhibitory neural and hormonal controls of HPA output are integrated, adaptations of the axis to chronic stress are effected, and how endocrine abnormalities may contribute to stress-related psychiatric illnesses in which mPFC dysfunction is implicated.
TL;DR: Results indicate that recently generated adult-born olfactory interneurons undergo different experience-dependent synaptic modifications compared with their pre-existing mature neighbors and provide a possible substrate for adult neurogenesis–dependent olfaction learning.
Abstract: To explore the functional consequences of adult neurogenesis in the mouse olfactory bulb, we investigated plasticity at glutamatergic synapses onto GABAergic interneurons We found that one subset of excitatory synapses onto adult-born granule cells showed long-term potentiation shortly after their arrival in the bulb This property faded as the newborn neurons matured These results indicate that recently generated adult-born olfactory interneurons undergo different experience-dependent synaptic modifications compared with their pre-existing mature neighbors and provide a possible substrate for adult neurogenesis-dependent olfactory learning
TL;DR: Prefrontal deficits in a subset of GABAergic mRNAs, including NPY, are dependent on the regional supply of BDNF, which in turn is fine-tuned through a microRNA (miRNA)-mediated mechanism.
TL;DR: It is suggested that GABAergic signaling can be targeted to mitigate the deleterious effects of apoE4 on neurogenesis, and restored neuronal maturation and neuroGenesis in apOE4-KI mice to normal levels.
TL;DR: It is concluded that gabapentin and pregabalin are not GABAergic and instead reduce the stimulated release of transmitters by binding at calcium channel alpha-delta (CaVa2-d) proteins.
Abstract: Gabapentin (Neurontin ) and pregabalin (Lyrica ) comprise an interesting class of drugs for chronic pain. These drugs differ structurally and mechanistically from other analgesics and also have efficacy in randomized trials for epileptic seizures and anxiety disorders. This paper highlights cellular and molecular mechanisms of these drugs that reduce pain. It is concluded that these drugs are not GABAergic and instead reduce the stimulated release of transmitters by binding at calcium channel alpha2-delta (CaVa2-d) proteins. The CaV nomenclature is useful to avoid confusion with unrelated adrenergic alpha receptors. Recent evidence suggests that CaVa2-d drugs also could reduce activity within certain cellular signaling pathways. The chemists who designed gabapentin and pregabalin endeavored to mimic the inhibitory neurotransmitter c-aminobutyric acid (GABA) in brain. However, later studies showed that this does not occur at relevant concentrations (see Section 3, below). Although sometimes called GABA derivatives or analogues (referring to chemical structure), this does not imply GABA-related pharmacology. Both compounds also differ from GABA because they readily cross membrane barriers via system L-amino acid transporters [36].
TL;DR: Results demonstrate a mutual suppression between the GABAergic APL neuron and olfactory learning, and emphasize the functional neuroplasticity of the inhibitory neurotransmitter system as a result of learning.
Abstract: GABAergic neurotransmitter systems are important for many cognitive processes, including learning and memory. We identified a single neuron in each hemisphere of the Drosophila brain, the anterior paired lateral (APL) neuron, as a GABAergic neuron that broadly innervated the mushroom bodies. Reducing GABA synthesis in the APL neuron enhanced olfactory learning, suggesting that the APL neuron suppressed learning by releasing the inhibitory neurotransmitter GABA. Functional optical-imaging experiments revealed that the APL neuron responded to both odor and electric-shock stimuli that was presented to the fly with increases of intracellular calcium and released neurotransmitter. Notably, a memory trace formed in the APL neuron by pairing odor with electric shock. This trace was detected as a reduced calcium response in the APL neuron after conditioning specifically to the trained odor. These results demonstrate a mutual suppression between the GABAergic APL neuron and olfactory learning, and emphasize the functional neuroplasticity of the GABAergic system as a result of learning.
TL;DR: In this article, four groups of pyramidal interneuron according to their expression of parvalbumin, cholecystokinin, axonal arborization density and long-range projections are described.
Abstract: The dendrites of pyramidal cells are active compartments capable of independent computations, input/output transformation and synaptic plasticity. Pyramidal cells in the CA1 area of the hippocampus receive 92% of their GABAergic input onto dendrites. How does this GABAergic input participate in dendritic computations of pyramidal cells? One key to understanding their contribution to dendritic computation lies in the timing of GABAergic input in relation to excitatory transmission, back-propagating action potentials, Ca(2+) spikes and subthreshold membrane dynamics. The issue is further complicated by the fact that dendritic GABAergic inputs originate from numerous distinct sources operating with different molecular machineries and innervating different subcellular domains of pyramidal cell dendrites. The GABAergic input from distinct sources is likely to contribute differentially to dendritic computations. In this review, I describe four groups of GABAergic interneuron according to their expression of parvalbumin, cholecystokinin, axonal arborization density and long-range projections. These four interneuron groups contain at least 12 distinct cell types, which innervate mainly or exclusively the dendrites of CA1 pyramidal cells. Furthermore, I summarize the different spike timing of distinct interneuron types during gamma, theta and ripple oscillations in vivo, and I discuss some of the open questions on how GABAergic input modulates dendritic operations in CA1 pyramidal cells.
TL;DR: This work shows that GABAergic neurons gating PS (PS-off neurons) are principally located in the ventrolateral periaqueductal gray and the dorsal part of the deep mesencephalic reticular nucleus immediately ventral to it (dDpMe), and proposes a revised model for PS control in which GABAergic PS-on and PS- off neurons localized in the vlPAG/dDPMe region play leading roles.
Abstract: Paradoxical sleep (PS) is a state characterized by cortical activation, rapid eye movements and muscle atonia. Fifty years after its discovery, the neuronal network responsible for the genesis of PS has been only partially identified. We recently proposed that GABAergic neurons would have a pivotal role in that network. To localize these GABAergic neurons, we combined immunohistochemical detection of Fos with non-radioactive in situ hybridization of GAD67 mRNA (GABA synthesis enzyme) in control rats, rats deprived of PS for 72 h and rats allowed to recover after such deprivation. Here we show that GABAergic neurons gating PS (PS-off neurons) are principally located in the ventrolateral periaqueductal gray (vlPAG) and the dorsal part of the deep mesencephalic reticular nucleus immediately ventral to it (dDpMe). Furthermore, iontophoretic application of muscimol for 20 min in this area in head-restrained rats induced a strong and significant increase in PS quantities compared to saline. In addition, we found a large number of GABAergic PS-on neurons in the vlPAG/dDPMe region and the medullary reticular nuclei known to generate muscle atonia during PS. Finally, we showed that PS-on neurons triggering PS localized in the SLD are not GABAergic. Altogether, our results indicate that multiple populations of PS-on GABAergic neurons are distributed in the brainstem while only one population of PS-off GABAergic neurons localized in the vlPAG/dDpMe region exist. From these results, we propose a revised model for PS control in which GABAergic PS-on and PS-off neurons localized in the vlPAG/dDPMe region play leading roles.
TL;DR: Cellular and network DA actions in PFC are region and layer specific and may depend on precise cellular interactions.
Abstract: Mesocortical dopamine (DA) is a key neurotransmitter in cognitive processes and is involved in schizophrenia and antipsychotic drug action. DA exerts a highly complex modulation of network activity in prefrontal cortex (PFC), possibly due to the recruitment of multiple signaling pathways and to specialized cellular localizations of DA receptors in cortical microcircuits. Using double in situ hybridization, we quantitatively assessed the expression of D(1) and D(2) receptor messenger RNAs (mRNAs) in pyramidal and gamma-aminobutyric acidergic (GABAergic) neurons of rat PFC. The proportion of pyramidal and GABA cells expressing these transcripts shows great regional variability in PFC, with little overlap (layer V). More pyramidal and GABA cells express D(1) than D(2) receptors. D(1) receptors are expressed by a greater proportion of GABA than pyramidal neurons, yet the number of D(1)-positive pyramidal cells outnumbers D(1)-positive interneurons due to the greater abundance of pyramidal neurons. Occasional PFC cells show high levels of mRNA, similar to those in striatal neurons. Finally, pyramidal and GABAergic cells expressing the same transcript were almost never found in close apposition, yet D(2)-containing pyramidal neurons were often found close to non-D(2) GABA neurons. Thus, cellular and network DA actions in PFC are region and layer specific and may depend on precise cellular interactions.
TL;DR: It is shown here that the connectivity and synaptic differentiation of GABAergic interneurons that mediate presynaptic inhibition is directed by their sensory targets, and that in the absence of sensory terminals these GABAergic neurons shun other available targets, fail to undergo presYNaptic differentiation, and withdraw axons from the ventral spinal cord.
TL;DR: Bilateral MGE cell grafts in epileptic mice lacking a Shaker-like potassium channel resulted in significant reductions in the duration and frequency of spontaneous electrographic seizures, suggesting that MGE-derived interneurons could be used to ameliorate abnormal excitability and possibly act as an effective strategy in the treatment of epilepsy.
Abstract: Epilepsy, a disease characterized by abnormal brain activity, is a disabling and potentially life-threatening condition for nearly 1% of the world population. Unfortunately, modulation of brain excitability using available antiepileptic drugs can have serious side effects, especially in the developing brain, and some patients can only be improved by surgical removal of brain regions containing the seizure focus. Here, we show that bilateral transplantation of precursor cells from the embryonic medial ganglionic eminence (MGE) into early postnatal neocortex generates mature GABAergic interneurons in the host brain. In mice receiving MGE cell grafts, GABA-mediated synaptic and extrasynaptic inhibition onto host brain pyramidal neurons is significantly increased. Bilateral MGE cell grafts in epileptic mice lacking a Shaker-like potassium channel (a gene mutated in one form of human epilepsy) resulted in significant reductions in the duration and frequency of spontaneous electrographic seizures. Our findings suggest that MGE-derived interneurons could be used to ameliorate abnormal excitability and possibly act as an effective strategy in the treatment of epilepsy.
01 Jan 2009
TL;DR: Four groups of GABAergic interneuron are described according to their expression of parvalbumin, cholecystokinin, axonal arborization density and long‐range projections, which contain at least 12 distinct cell types, which innervate mainly or exclusively the dendrites of CA1 pyramidal cells.
Abstract: The dendrites of pyramidal cells are active compartments capable of independent computations, input⁄output transformation and synaptic plasticity. Pyramidal cells in the CA1 area of the hippocampus receive 92% of their GABAergic input onto dendrites. How does this GABAergic input participate in dendritic computations of pyramidal cells? One key to understanding their contribution to dendritic computation lies in the timing of GABAergic input in relation to excitatory transmission, back-propagating action potentials, Ca 2+ spikes and subthreshold membrane dynamics. The issue is further complicated by the fact that dendritic GABAergic inputs originate from numerous distinct sources operating with different molecular machineries and innervating different subcellular domains of pyramidal cell dendrites. The GABAergic input from distinct sources is likely to contribute differentially to dendritic computations. In this review, I describe four groups of GABAergic interneuron according to their expression of parvalbumin, cholecystokinin, axonal arborization density and long-range projections. These four interneuron groups contain at least 12 distinct cell types, which innervate mainly or exclusively the dendrites of CA1 pyramidal cells. Furthermore, I summarize the different spike timing of distinct interneuron types during gamma, theta and ripple oscillations in vivo, and I discuss some of the open questions on how GABAergic input modulates dendritic operations in CA1 pyramidal cells.
TL;DR: In this paper, anterograde tract tracing from the lateral habenula (LHb) was used to investigate the relative selectivity of LHb synapses onto GABA versus DA VTA neurons.
Abstract: Ventral tegmental area (VTA) dopamine (DA) neurons and their forebrain projections are critically involved in reward processing and cognitive functions. Descending projections from the lateral habenula (LHb) play a central role in inhibiting DA cell activity in response to the absence of expected rewards. As LHb efferents are reportedly glutamatergic, their ability to inhibit DA cells would theoretically require a disynaptic connection involving VTA GABA neurons and their local collateral inputs to DA cells. We therefore used anterograde tract-tracing from the LHb to investigate the relative selectivity of LHb synapses onto GABA versus DA VTA neurons. LHb axons were visualized using immunoperoxidase, and DA and GABA cells were marked by immunogold-silver labeling for tyrosine hydroxylase (TH) or GABA, respectively. By ultrastructural analysis, 16% of LHb axons were observed to form synaptic contacts in the VTA, and most of these were of an intermediate morphological type that did not exhibit definitive asymmetric or symmetric character. LHb axons synaptically targeted TH- and GABA-labeled dendrites to a comparable extent (45 and 52% observed incidence, respectively). Pre-embedding immunogold labeling for the vesicular glutamate transporter type 2 and post-embedding immunogold staining for GABA confirmed that approximately 85% of LHb terminals were glutamatergic and not GABAergic. These results suggest that the robust inhibition of DA cells evoked by the LHb is unlikely to arise from a selective innervation of VTA GABA neurons. Moreover, the LHb may mediate a direct excitation of DA cells that is over-ridden by indirect inhibition originating from an extrinsic source.
TL;DR: The importance of promoter IV-dependent Bdnf transcription in GABAergic function is demonstrated and an unexpected regulation of STDP in the PFC by BDNF is revealed, demonstrating the importance of activity-dependent brain-derived neurotrophic factor transcription.
Abstract: Transcription of Bdnf is controlled by multiple promoters, which drive expression of multiple transcripts encoding for the same protein. Promoter IV contributes significantly to activity-dependent brain-derived neurotrophic factor (BDNF) transcription. We have generated promoter IV mutant mice (BDNF-KIV) by inserting a GFP-STOP cassette within the Bdnf exon IV locus. This genetic manipulation results in disruption of promoter IV-mediated Bdnf expression. BDNF-KIV animals exhibited significant deficits in GABAergic interneurons in the prefrontal cortex (PFC), particularly those expressing parvalbumin, a subtype implicated in executive function and schizophrenia. Moreover, disruption of promoter IV-driven Bdnf transcription impaired inhibitory but not excitatory synaptic transmission recorded from layer V pyramidal neurons in the PFC. The attenuation of GABAergic inputs resulted in an aberrant appearance of spike-timing-dependent synaptic potentiation (STDP) in PFC slices derived from BDNF-KIV, but not wild-type littermates. These results demonstrate the importance of promoter IV-dependent Bdnf transcription in GABAergic function and reveal an unexpected regulation of STDP in the PFC by BDNF.
TL;DR: Recording and labeling neurons during natural sleep–wake states in head-fixed rats revealed that GABAergic neurons would play similar or reciprocal roles to other cholinergic and glutamatergic BF neurons in regulating cortical activity and muscle tone along with behavior across sleep-wake states.
Abstract: Whereas basal forebrain (BF) cholinergic neurons are known to participate in processes of cortical activation during wake (W) and paradoxical sleep (PS or P, also called REM sleep), codistributed GABAergic neurons have been thought to participate in processes of cortical deactivation and slow-wave sleep (SWS or S). To learn the roles the GABAergic neurons might play, in relation to cholinergic and glutamatergic neurons, we juxtacellularly recorded and labeled neurons during natural sleep-wake states in head-fixed rats. Neurobiotin (Nb)-labeled cells were identified immunohistochemically as choline acetyltransferase (ChAT)+, glutamic acid decarboxylase (GAD)+, or ChAT-/GAD-. Of the latter, some were identified as glutamatergic by immunostaining of their terminals with the vesicular glutamate transporter (VGluT2). In contrast to ChAT+ neurons, which all discharged maximally during W and PS, GAD+ neurons comprised multiple sleep-wake subgroups. Some GABAergic neurons discharged maximally during W and PS, as WP-max active cells (36%), and in positive correlation with gamma electroencephalographic (EEG) activity. Some discharged maximally during SWS, as S-max active cells (28%), and in positive correlation with delta EEG activity. Others increased their discharge progressively during sleep to discharge maximally during PS, as P-max active cells (36%), and in negative association with electromyographic (EMG) activity. ChAT-/GAD- cells comprised WP-max (46%), S-max (17%), P-max (17%), and W-max active cells (14%), whose discharge was positively correlated with EMG activity. GABAergic neurons would thus play similar or reciprocal roles to other cholinergic and glutamatergic BF neurons in regulating cortical activity and muscle tone along with behavior across sleep-wake states.
TL;DR: Adult-born granule cells in human amyloid precursor protein (hAPP) transgenic mice, an AD model, showed greater dendritic length, spine density, and functional responses than did controls early in development, but were impaired morphologically and functionally during later maturation.
TL;DR: Valproic acid (VPA) may disrupt a balance between excitatory and inhibitory neuronal activities through its epigenetic effect.
TL;DR: Upregulation of many components of the GABAergic system in cerebellum, but not in cortex is found, consistent with the cerebellar phenotype of FXTAS patients and has implications for the mechanism causative of differential gene expression.
TL;DR: Increased awareness of SPS among practicing physicians is necessary to recognize the disease early and prevent permanent disability, and new immunomodulating agents are being explored to treat difficult cases and to induce long-lasting remissions.
Abstract: Stiff person syndrome (SPS) varies from mild to severe, but if untreated it can be progressive and disabling. Although progress has been made in understanding and treating SPS, the disease remains underdiagnosed, delaying treatment. Antibodies against glutamic acid decarboxylase provide an excellent diagnostic marker, but their role in disease pathogenesis is uncertain. Research focused on identifying new autoantigens has provided evidence that gamma-aminobutyric acid (GABA)(A) receptor-associated protein (GABARAP), a 14-kD protein localized at the postsynaptic regions of GABAergic synapses, is an antigenic target. Circulating anti-GABARAP antibodies that inhibit GABA(A) receptor expression on GABAergic neurons have been found in up to 65% of SPS patients. The impairment of GABAergic pathways and reduction of brain GABA results in clinical manifestations of stiffness, spasms, and phobias. Increased awareness of SPS among practicing physicians is necessary to recognize the disease early and prevent permanent disability. Most patients with SPS respond to GABA-enhancing drugs, but the high doses required cause unacceptable adverse effects. The disease clearly responds to intravenous immunoglobulin, but repeated infusions are needed to maintain response. New immunomodulating agents are being explored to treat difficult cases and to induce long-lasting remissions.