Showing papers on "GABAergic published in 2013"
TL;DR: The role of GABAergic interneurons in cortical wiring, plasticity, and network activity during pre- and postnatal development and psychiatric diseases that may be considered at least in part developmental disorders of the GABAergic system are discussed.
378 citations
TL;DR: The findings suggest that the effect of an inhibitory synapse can be as compartmentalized as that of an excitatory synapse, provided that the synapses are localized on spine heads.
Abstract: γ-aminobutyric acid-mediated (GABAergic) inhibition plays a critical role in shaping neuronal activity in the neocortex. Numerous experimental investigations have examined perisomatic inhibitory synapses, which control action potential output from pyramidal neurons. However, most inhibitory synapses in the neocortex are formed onto pyramidal cell dendrites, where theoretical studies suggest they may focally regulate cellular activity. The precision of GABAergic control over dendritic electrical and biochemical signaling is unknown. By using cell type-specific optical stimulation in combination with two-photon calcium (Ca(2+)) imaging, we show that somatostatin-expressing interneurons exert compartmentalized control over postsynaptic Ca(2+) signals within individual dendritic spines. This highly focal inhibitory action is mediated by a subset of GABAergic synapses that directly target spine heads. GABAergic inhibition thus participates in localized control of dendritic electrical and biochemical signaling.
270 citations
TL;DR: It is concluded that the vast majority of human cortical interneurons are produced in the ganglionic eminences, including an enormous contribution from non-epithelial SVZ stem cells.
Abstract: GABAergic cortical interneurons have important roles in the computations of neural circuits, but their developmental origin in primates is controversial. Here the authors characterize neural stem cell and progenitor cell organization in the developing human ganglionic eminences and reveal that, just as in rodents, they give rise to a majority of cortical GABAergic neurons.
255 citations
TL;DR: This review shows that the antiepileptic effects of loop diuretics described in the pertinent literature are based on widely heterogeneous mechanisms ranging from actions on both neuronal NKCC1 and KCC2 to modulation of the brain extracellular volume fraction.
245 citations
TL;DR: 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, which suggests a role for NO in the coordination of local pre- and post-synaptic function during plasticity at individual synapses.
Abstract: 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.
226 citations
TL;DR: In this article, the authors provide an overview of the mechanisms used by GABAergic interneurons to reach their final position, with an emphasis on the final steps of this process.
179 citations
TL;DR: It is concluded that regional neurotransmitter concentrations in a network node strongly predict network but not global brain iFC.
176 citations
TL;DR: The first characterization of GABA neurons in the DRN that monosynaptically inhibit 5-HT neurons is provided and their key role in neuroplastic processes underlying the development of social avoidance is revealed.
Abstract: Serotonin (5-HT) modulates neural responses to socioaffective cues and can bias approach or avoidance behavioral decisions, yet the cellular mechanisms underlying its contribution to the regulation of social experiences remain poorly understood. We hypothesized that GABAergic neurons in the dorsal raphe nucleus (DRN) may participate in socioaffective regulation by controlling serotonergic tone during social interaction. We tested this hypothesis using whole-cell recording techniques in genetically identified DRN GABA and 5-HT neurons in mice exposed to social defeat, a model that induces long-lasting avoidance behaviors in a subset of mice responsive to serotonergic antidepressants. Our results revealed that social defeat engaged DRN GABA neurons and drove GABAergic sensitization that strengthened inhibition of 5-HT neurons in mice that were susceptible, but not resilient to social defeat. Furthermore, optogenetic silencing of DRN GABA neurons disinhibited neighboring 5-HT neurons and prevented the acquisition of social avoidance in mice exposed to a social threat, but did not affect a previously acquired avoidance phenotype. We provide the first characterization of GABA neurons in the DRN that monosynaptically inhibit 5-HT neurons and reveal their key role in neuroplastic processes underlying the development of social avoidance.
170 citations
TL;DR: This review will focus primarily on GABAergic interneurons of the mammalian cerebral cortex from a developmental standpoint and place an emphasis on the transcriptional network of genes that play a role in the specification and maintenance of GABAergicinterneuron fate.
Abstract: GABAergic interneurons are inhibitory neurons of the nervous system that play a vital role in neural circuitry and activity. They are so named due to their release of the neurotransmitter gamma-aminobutyric acid (GABA), and occupy different areas of the brain. This review will focus primarily on GABAergic interneurons of the mammalian cerebral cortex from a developmental standpoint. There is a diverse amount of cortical interneuronal subtypes that may be categorized by a number of characteristics; this review will classify them largely by the protein markers they express. The developmental origins of GABAergic interneurons will be discussed, as well as factors that influence the complex migration routes that these interneurons must take in order to ultimately localize in the cerebral cortex where they will integrate with the neural circuitry set in place. This review will also place an emphasis on the transcriptional network of genes that play a role in the specification and maintenance of GABAergic interneuron fate. Gaining an understanding of the different aspects of cortical interneuron development and specification, especially in humans, has many useful clinical applications that may serve to treat various neurological disorders linked to alterations in interneuron populations.
153 citations
TL;DR: The results demonstrated that tiagabine, and hence elevated endogenous GABA levels causes, an elevation of baseline beta power, enhanced beta-ERD and reduced PMBR, but no modulation of MRGS, suggesting that beta- ERD may be a GABAA receptor mediated process while PMBR may be GABAB receptor mediated.
151 citations
TL;DR: Support is provided for altered glutamatergic and GABAergic function associated with illness course and cognitive and negative symptoms in schizophrenia and the importance of studies that combine MRS measurements of NAAG, GABA, and Glu for a more comprehensive neurochemical characterization of schizophrenia is highlighted.
Abstract: The major excitatory and inhibitory neurotransmitters, glutamate (Glu) and gamma-aminobutyric acid (GABA), respectively, are implicated in the pathophysiology of schizophrenia. N-acetyl-aspartyl-glutamate (NAAG), a neuropeptide that modulates the Glu system, may also be altered in schizophrenia. This study investigated GABA, Glu + glutamine (Glx), and NAAG levels in younger and older subjects with schizophrenia. Forty-one subjects, 21 with chronic schizophrenia and 20 healthy controls, participated in this study. Proton magnetic resonance spectroscopy (1H-MRS) was used to measure GABA, Glx, and NAAG levels in the anterior cingulate (AC) and centrum semiovale (CSO) regions. NAAG in the CSO was higher in younger schizophrenia subjects compared with younger control subjects. The opposite pattern was observed in the older groups. Glx was reduced in the schizophrenia group irrespective of age group and brain region. There was a trend for reduced AC GABA in older schizophrenia subjects compared with older control subjects. Poor attention performance was correlated to lower AC GABA levels in both groups. Higher levels of CSO NAAG were associated with greater negative symptom severity in schizophrenia. These results provide support for altered glutamatergic and GABAergic function associated with illness course and cognitive and negative symptoms in schizophrenia. The study also highlights the importance of studies that combine MRS measurements of NAAG, GABA, and Glu for a more comprehensive neurochemical characterization of schizophrenia.
TL;DR: It is proposed that long-range GABAergic neurons play a critical role in the temporal coordination of neuronal activity in distant brain areas via disinhibition.
TL;DR: Reducing GABAergic inhibition with RO4938581 can reverse functional and neuromorphological deficits of TS mice by facilitating brain plasticity and support the potential therapeutic use of selective GABAA α5 NAMs to treat cognitive dysfunction in DS.
Abstract: Down syndrome (DS) is associated with neurological complications, including cognitive deficits that lead to impairment in intellectual functioning. Increased GABA-mediated inhibition has been proposed as a mechanism underlying deficient cognition in the Ts65Dn (TS) mouse model of DS. We show that chronic treatment of these mice with RO4938581 (3-bromo-10-(difluoromethyl)-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]diazepine), a selective GABA A α5 negative allosteric modulator (NAM), rescued their deficits in spatial learning and memory, hippocampal synaptic plasticity, and adult neurogenesis. We also show that RO4938581 normalized the high density of GABAergic synapse markers in the molecular layer of the hippocampus of TS mice. In addition, RO4938581 treatment suppressed the hyperactivity observed in TS mice without inducing anxiety or altering their motor abilities. These data demonstrate that reducing GABAergic inhibition with RO4938581 can reverse functional and neuromorphological deficits of TS mice by facilitating brain plasticity and support the potential therapeutic use of selective GABA A α5 NAMs to treat cognitive dysfunction in DS.
TL;DR: Using two-photon Ca2+ imaging of axonal boutons in hippocampal CA1 of behaving mice, it is found that populations of septo-hippocampal GABAergic boutons were activated during locomotion and salient sensory events; sensory responses scaled with stimulus intensity and were abolished by anesthesia.
Abstract: Hippocampal interneurons receive GABAergic input from the medial septum. Using two-photon Ca(2+) imaging of axonal boutons in hippocampal CA1 of behaving mice, we found that populations of septo-hippocampal GABAergic boutons were activated during locomotion and salient sensory events; sensory responses scaled with stimulus intensity and were abolished by anesthesia. We found similar activity patterns among boutons with common putative postsynaptic targets, with low-dimensional bouton population dynamics being driven primarily by presynaptic spiking.
TL;DR: This work identifies the GABAergic interneuron as a potential target for smoking cessation drug development and demonstrates that both positive and negative motivational values are transmitted through the dopamine neuron, but that the concerted activity of DA and GABA systems is necessary for the reinforcing actions of nicotine through burst firing of DA neurons.
Abstract: Smoking is the most important preventable cause of mortality and morbidity worldwide. This nicotine addiction is mediated through the nicotinic acetylcholine receptor (nAChR), expressed on most neurons, and also many other organs in the body. Even within the ventral tegmental area (VTA), the key brain area responsible for the reinforcing properties of all drugs of abuse, nicotine acts on several different cell types and afferents. Identifying the precise action of nicotine on this microcircuit, in vivo, is important to understand reinforcement, and finally to develop efficient smoking cessation treatments. We used a novel lentiviral system to re-express exclusively high-affinity nAChRs on either dopaminergic (DAergic) or γ-aminobutyric acid-releasing (GABAergic) neurons, or both, in the VTA. Using in vivo electrophysiology, we show that, contrary to widely accepted models, the activation of GABA neurons in the VTA plays a crucial role in the control of nicotine-elicited DAergic activity. Our results demonstrate that both positive and negative motivational values are transmitted through the dopamine (DA) neuron, but that the concerted activity of DA and GABA systems is necessary for the reinforcing actions of nicotine through burst firing of DA neurons. This work identifies the GABAergic interneuron as a potential target for smoking cessation drug development.
TL;DR: The results help to understand the mechanisms underlying the regulation of GABAergic tonic conductance in the hippocampus and can help to develop improved therapeutic strategies for neurological and psychiatric disorders.
Abstract: Tonic γ-aminobutyric acid (GABA)A receptor-mediated signalling controls neuronal network excitability in the hippocampus. Although the extracellular concentration of GABA (e[GABA]) is critical in determining tonic conductances, knowledge on how e[GABA] is regulated by different GABA transporters (GATs) in vivo is limited. Therefore, we studied the role of GATs in the regulation of hippocampal e[GABA] using in vivo microdialysis in freely moving rats. Here we show that GAT-1, which is predominantly presynaptically located, is the major GABA transporter under baseline, quiescent conditions. Furthermore, a significant contribution of GAT-3 in regulating e[GABA] was revealed by administration of the GAT-3 inhibitor SNAP-5114 during simultaneous blockade of GAT-1 by NNC-711. Thus, the GABA transporting activity of GAT-3 (the expression of which is confined to astrocytes) is apparent under conditions in which GAT-1 is blocked. However, sustained neuronal activation by K(+)-induced depolarization caused a profound spillover of GABA into the extrasynaptic space and this increase in e[GABA] was significantly potentiated by sole blockade of GAT-3 (i.e. even when uptake of GAT-1 is intact). Furthermore, experiments using tetrodotoxin to block action potentials revealed that GAT-3 regulates extrasynaptic GABA levels from action potential-independent sources when GAT-1 is blocked. Importantly, changes in e[GABA] resulting from both GAT-1 and GAT-3 inhibition directly precipitate changes in tonic conductances in dentate granule cells as measured by whole-cell patch-clamp recording. Thus, astrocytic GAT-3 contributes to the regulation of e[GABA] in the hippocampus in vivo and may play an important role in controlling the excitability of hippocampal cells when network activity is increased.
TL;DR: It is shown that GABAergic signaling governs the polarity of STDP, because blockade of GABAA receptors was able to completely reverse the temporal order of plasticity at corticostriatal synapses in rats and mice.
Abstract: The spike-timing-dependent plasticity (STDP), a synaptic learning rule for encoding learning and memory, relies on relative timing of neuronal activity on either side of the synapse. GABAergic signaling has been shown to control neuronal excitability and consequently the spike timing, but whether GABAergic circuits rule the STDP remained unknown. Here we show that GABAergic signaling governs the polarity of STDP, because blockade of GABAA receptors was able to completely reverse the temporal order of plasticity at corticostriatal synapses in rats and mice. GABA controls the polarity of STDP in both striatopallidal and striatonigral output neurons. Biophysical simulations and experimental investigations suggest that GABA controls STDP polarity through depolarizing effects at distal dendrites of striatal output neurons by modifying the balance of two calcium sources, NMDARs and voltage-sensitive calcium channels. These findings establish a central role for GABAergic circuits in shaping STDP and suggest that GABA could operate as a Hebbian/anti-Hebbian switch.
TL;DR: It is demonstrated that vesicular γ-aminobutyric acid (GABA) transporter (VGAT) presynaptic bouton density is unaffected in human preclinical and end-stage AD and in APP/PS1 transgenic mice, indicating that GABAergic synapses are preserved in human AD and mouse TGs.
TL;DR: The data indicate that therapeutic strategies to reduce IPN GABAergic neuron excitability during nicotine withdrawal, for example, by activating nicotinic receptors on somatostatin interneurons, may be beneficial for alleviating withdrawal symptoms and facilitating smoking cessation.
TL;DR: The results show that mPFC inhibitory networks are affected by chronic stress and suggest that structural plasticity may be an important feature of stress-related psychiatric disorders where this cortical region, specially their GABAergic system, is altered.
Abstract: Chronic stress in experimental animals induces dendritic atrophy and decreases spine density in principal neurons of the medial prefrontal cortex (mPFC) This structural plasticity may play a neuroprotective role and underlie stress-induced behavioral changes Different evidences indicate that the prefrontocortical GABA system is also altered by stress and in major depression patients In the amygdala, chronic stress induces dendritic remodeling both in principal neurons and in interneurons However, it is not known whether similar structural changes occur in mPFC interneurons The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) may mediate these changes, because it is known to influence the dendritic organization of adult cortical interneurons We have analyzed the dendritic arborization and spine density of mPFC interneurons in adult mice after 21 days of restraint stress and have found dendritic hypertrophy in a subpopulation of interneurons identified mainly as Martinotti cells This aversive experience also decreases the number of glutamate decarboxylase enzyme, 67 kDa isoform (GAD67) expressing somata, without affecting different parameters related to apoptosis, but does not alter the number of interneurons expressing PSA-NCAM Quantitative retrotranscription-polymerase chain reaction (qRT-PCR) analysis of genes related to general and inhibitory neurotransmission and of PSA synthesizing enzymes reveals increases in the expression of NCAM, synaptophysin and GABA(A)α1 Together these results show that mPFC inhibitory networks are affected by chronic stress and suggest that structural plasticity may be an important feature of stress-related psychiatric disorders where this cortical region, specially their GABAergic system, is altered
TL;DR: It is found that blocking kappa opioid receptors (KORs) within the VTA prior to forced-swim stress prevents reinstatement of cocaine seeking and suggests that KORs may represent a useful therapeutic target for treatment of stress-triggered relapse in substance abuse.
TL;DR: Results strongly suggest that these PS-off neurons gate the activation of the PS-on glutamatergic neurons located in the sublaterodorsal tegmental nucleus (SLD) and responsible for cortical activation and muscle atonia via descending projections to GABA/glycinergic neurons localized in the ventral medullary reticular nuclei.
TL;DR: Channelrhodopsin is used to stimulate GABAergic axons from the basal forebrain selectively and it is shown that this stimulation generates reliable inhibitory responses in GCs, indicating an important role of these inhibitory afferents in olfactory processing.
Abstract: Granule cells (GCs) are the most abundant inhibitory neuronal type in the olfactory bulb and play a critical role in olfactory processing. GCs regulate the activity of principal neurons, the mitral cells, through dendrodendritic synapses, shaping the olfactory bulb output to other brain regions. GC excitability is regulated precisely by intrinsic and extrinsic inputs, and this regulation is fundamental for odor discrimination. Here, we used channelrhodopsin to stimulate GABAergic axons from the basal forebrain selectively and show that this stimulation generates reliable inhibitory responses in GCs. Furthermore, selective in vivo inhibition of GABAergic neurons in the basal forebrain by targeted expression of designer receptors exclusively activated by designer drugs produced a reversible impairment in the discrimination of structurally similar odors, indicating an important role of these inhibitory afferents in olfactory processing.
TL;DR: It is speculated that impairment in the GABAergic system critically contributes to an increase in the ratio between synaptic excitation and inhibition, which in genetically predisposed individuals may alter cortical circuits responsible for emotional, communication and social impairments at the core of ASD.
Abstract: The biological mechanisms of autism spectrum disorders (ASDs) are largely unknown in spite of extensive research. ASD is characterized by altered function of multiple brain areas including the temporal cortex and by an increased synaptic excitation:inhibition ratio. While numerous studies searched for evidence of increased excitation in ASD, fewer have investigated the possibility of reduced inhibition. We characterized the cortical γ-amino butyric acid (GABA)ergic system in the rat temporal cortex of an ASD model [offspring of mothers prenatally injected with valproic acid (VPA)], by monitoring inhibitory post-synaptic currents (IPSCs) with patch-clamp. We found that numerous features of inhibition were severely altered in VPA animals compared to controls. Among them were the frequency of miniature IPSCs, the rise time and decay time of electrically-evoked IPSCs, the slope and saturation of their input/output curves, as well as their modulation by adrenergic and muscarinic agonists and by the synaptic GABAA receptor allosteric modulator zolpidem (but not by the extra-synaptic modulator gaboxadol). Our data suggest that both pre- and post-synaptic, but not extra-synaptic, inhibitory transmission is impaired in the offspring of VPA-injected mothers. We speculate that impairment in the GABAergic system critically contributes to an increase in the ratio between synaptic excitation and inhibition, which in genetically predisposed individuals may alter cortical circuits responsible for emotional, communication and social impairments at the core of ASD.
TL;DR: The present review is aimed to discuss the role of GABA(B) receptors and the possible outcomes of GABAB receptor modulation in CNS disorders.
Abstract: Glutamate and γ-aminobutyric acid (GABA) are the major excitatory and inhibitory neurotransmitter systems, respectively in the central nervous system (CNS). Dysregulation, in any of these or both, has been implicated in various CNS disorders. GABA acts via ionotropic (GABA(A) and GABA(C) receptor) and metabotropic (GABA(B)) receptor. Dysregulation of GABAergic signaling and alteration in GABA(B) receptor expression has been implicated in various CNS disorders. Clinically, baclofen-a GABA(B) receptor agonist is available for the treatment of spasticity, dystonia etc., associated with various neurological disorders. Moreover, GABAB receptor ligands has also been suggested to be beneficial in various neuropsychiatric and neurodegenerative disorders. The present review is aimed to discuss the role of GABA(B) receptors and the possible outcomes of GABA(B) receptor modulation in CNS disorders.
TL;DR: It is shown for the first time that hippocampal GABAergic function is impaired by pathological tau protein, leading to altered synaptic plasticity and severe memory deficits in aged JNPL3 (BL6) mice.
Abstract: Tau is a microtubule stabilizing protein and is mainly expressed in neurons. Tau aggregation into oligomers and tangles is considered an important pathological event in tauopathies, such as frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Tauopathies are also associated with deficits in synaptic plasticity such as long-term potentiation (LTP), but the specific role of tau in the manifestation of these deficiencies is not well-understood. We examined long lasting forms of synaptic plasticity in JNPL3 (BL6) mice expressing mutant tau that is identified in some inherited FTDs. We found that aged (>12 months) JNPL3 (BL6) mice exhibit enhanced hippocampal late-phase (L-LTP), while young JNPL3 (BL6) mice (age 6 months) displayed normal L-LTP. This enhanced L-LTP in aged JNPL3 (BL6) mice was rescued with the GABAAR agonist, zolpidem, suggesting a loss of GABAergic function. Indeed, we found that mutant mice displayed a reduction in hippocampal GABAergic interneurons. Finally, we also found that expression of mutant tau led to severe sensorimotor-gating and hippocampus-dependent memory deficits in the aged JNPL3 (BL6) mice. We show for the first time that hippocampal GABAergic function is impaired by pathological tau protein, leading to altered synaptic plasticity and severe memory deficits. Increased understanding of the molecular mechanisms underlying the synaptic failure in AD and FTD is critical to identifying targets for therapies to restore cognitive deficiencies associated with tauopathies.
TL;DR: Significant group effects for protein levels of the α2-, β1- and ɛ-subunits across treatment groups are found and new avenues for treatment, such as the use of neurosteroids to promote GABA modulation, could potentially ameliorate GABAergic dysfunction in these disorders.
Abstract: There is abundant evidence that dysfunction of the γ-aminobutyric acid (GABA)ergic signaling system is implicated in the pathology of schizophrenia and mood disorders. Less is known about the alterations in protein expression of GABA receptor subunits in brains of subjects with schizophrenia and mood disorders. We have previously demonstrated reduced expression of GABAB receptor subunits 1 and 2 (GABBR1 and GABBR2) in the lateral cerebella of subjects with schizophrenia, bipolar disorder and major depressive disorder. In the current study, we have expanded these studies to examine the mRNA and protein expression of 12 GABAA subunit proteins (α1, α2, α3, α5, α6, β1, β2, β3, δ, ɛ, γ2 and γ3) in the lateral cerebella from the same set of subjects with schizophrenia (N=9–15), bipolar disorder (N=10–15) and major depression (N=12–15) versus healthy controls (N=10–15). We found significant group effects for protein levels of the α2-, β1- and ɛ-subunits across treatment groups. We also found a significant group effect for mRNA levels of the α1-subunit across treatment groups. New avenues for treatment, such as the use of neurosteroids to promote GABA modulation, could potentially ameliorate GABAergic dysfunction in these disorders.
TL;DR: These findings establish ganglionic eminence–dependent rules for early synaptic integration programs of distinct interneuron cohorts, including parvalbumin- and cholecystokinin-expressing basket cells.
Abstract: Disrupted excitatory synapse maturation in GABAergic interneurons may promote neuropsychiatric disorders such as schizophrenia. However, establishing developmental programs for nascent synapses in GABAergic cells is confounded by their sparsity, heterogeneity and late acquisition of subtype-defining characteristics. We investigated synaptic development in mouse interneurons targeting cells by lineage from medial ganglionic eminence (MGE) or caudal ganglionic eminence (CGE) progenitors. MGE-derived interneuron synapses were dominated by GluA2-lacking AMPA-type glutamate receptors (AMPARs), with little contribution from NMDA-type receptors (NMDARs) throughout development. In contrast, CGE-derived cell synapses had large NMDAR components and used GluA2-containing AMPARs. In neonates, both MGE- and CGE-derived interneurons expressed primarily GluN2B subunit-containing NMDARs, which most CGE-derived interneurons retained into adulthood. However, MGE-derived interneuron NMDARs underwent a GluN2B-to-GluN2A switch that could be triggered acutely with repetitive synaptic activity. Our findings establish ganglionic eminence-dependent rules for early synaptic integration programs of distinct interneuron cohorts, including parvalbumin- and cholecystokinin-expressing basket cells.
TL;DR: It is demonstrated that DBS in the nucleus accumbens shell, but not the core, attenuates cocaine priming-induced reinstatement of drug seeking, an animal model of relapse, in male Sprague Dawley rats.
Abstract: Accumbal deep brain stimulation (DBS) is a promising therapeutic modality for the treatment of addiction. Here, we demonstrate that DBS in the nucleus accumbens shell, but not the core, attenuates cocaine priming-induced reinstatement of drug seeking, an animal model of relapse, in male Sprague Dawley rats. Next, we compared DBS of the shell with pharmacological inactivation. Results indicated that inactivation using reagents that influenced (lidocaine) or spared (GABA receptor agonists) fibers of passage blocked cocaine reinstatement when administered into the core but not the shell. It seems unlikely, therefore, that intrashell DBS influences cocaine reinstatement by inactivating this nucleus or the fibers coursing through it. To examine potential circuit-wide changes, c-Fos immunohistochemistry was used to examine neuronal activation following DBS of the nucleus accumbens shell. Intrashell DBS increased c-Fos induction at the site of stimulation as well as in the infralimbic cortex, but had no effect on the dorsal striatum, prelimbic cortex, or ventral pallidum. Recent evidence indicates that accumbens DBS antidromically stimulates axon terminals, which ultimately activates GABAergic interneurons in cortical areas that send afferents to the shell. To test this hypothesis, GABA receptor agonists (baclofen/muscimol) were microinjected into the anterior cingulate, and prelimbic or infralimbic cortices before cocaine reinstatement. Pharmacological inactivation of all three medial prefrontal cortical subregions attenuated the reinstatement of cocaine seeking. These results are consistent with DBS of the accumbens shell attenuating cocaine reinstatement via local activation and/or activation of GABAergic interneurons in the medial prefrontal cortex via antidromic stimulation of cortico-accumbal afferents.
TL;DR: It is shown that DBI mediates endogenous nucleus-specific BZ-mimicking ("endozepine") roles to modulate nRT function and suppress thalamocortical oscillations, which might serve as a therapy for epilepsy and other neurological disorders.