GABA Structure, Function, Physiology, and Dysfunction
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Gamma-aminobutyric acid (GABA) is the principal inhibitory and abundant neurotransmitter in the mammalian nervous system (Figure 1). Although GABAergic interneurons, each with distinct morphological, physiological, and expression patterns account for less than 30% of cells in the cortex, approximately 60 – 70% of synapses in the central nervous system are proposed to be GABAergic, and are considered crucial for information processing. GABA signaling is essential for the maturation of the nervous system, synaptic plasticity, fine-tuning of neural circuits, sensory processing, and much more. Significantly, disruptions in GABA neurotransmission are linked to multiple neurologic and psychiatric disorders those in turn fundamentally inform the development of pharmacological interventions to treat such disorders.
The GABA interneurons are widely distributed in the nervous system and, as mentioned mediate most of the inhibitory input to neurons, whereas glutamate, another ubiquitous neurotransmitter in the nervous system is responsible for majority of the excitatory input. The maintenance of the optimal balance of excitatory/inhibitory (E/I) neurotransmission is important for proper cortical function and alterations in E/I equilibrium have been linked to various psychiatric diseases. Of late it has become clearer that apart from dampening neuronal excitability, GABA signals serves to shape the response of the post-synaptic neurons and ensemble of neurons forming a coherent neural circuit. In this vain, the GABAergic interneurons have been identified by notions of graph theory as unique 'operational hubs', dynamically controlling cortical network activity in their sphere and refining the flow of information beyond. Mapping techniques have advanced this notion by constructing atlases of the anatomical and functional relationships of local and long-range GABAergic connections established between cortical and sub-cortical regions.
The cortex has an abundance of phenotypically unique, non-overlapping populations of GABA interneurons. These cells maintain distinctive electrophysiological and biochemical features and are suited to encode pre- and post-synaptic events underlying different functional correlates of behavior. Evidence links behavior with the properties of distinct cellular populations, as in the anterior cingulate cortex (ACC), the somatostatin (STT)- and parvalbumin (PV)-expressing interneurons exhibit spatiotemporally distinct kinetics in response to different aspects of reward stimuli. At the cellular level, dendrite-targeting GABA interneurons dynamically impact post-synaptic neurons by shaping their membrane oscillations and integrating their numerous synaptic inputs. Furthermore, GABA interneurons with distinct identities, alter calcium signals in dendrites of prefrontal cortex pyramidal cells, with profound implications for cortical information processing. GABA leverages multiple electrophysiological and biochemical modes of action in its arsenal to crucially contribute to the precise timing of neural signals, serving to engender, initiate and shape rhythmic activity in the brain. These interneurons dramatically and subtly influence activity by engaging in different modes of feedback and feedforward inhibition on different spatial and temporal scales. - enabling them to have a dynamic influence on principal (pyramidal) neurons and on other interneurons and networks of cellular circuits. This endows GABA interneurons with the capacity to make meaningful contributions to pre- and post-synaptic events that underlie synaptic plasticity and learning.
Advances combining noninvasive multimodal techniques have enabled examination of neural activity on broader, macroscopic levels. These techniques allow for changes in neurotransmitter levels to be studied in concert with cognate neurophysiological events that accompany functional states related to behavior or emotion. A recent meta-analysis of studies on healthy individuals, using proton magnetic resonance spectroscopy (1H-MRS) and task-related functional magnetic resonance imaging (fMRI) aimed to examine exactly such relationships. The study showed elevated GABA levels associated with reduced local neural activity in the anterior cingulate and medial prefrontal cortex during emotional processing, and in the occipital cortex during visual processing. A similar local result was not observed in the case of glutamate, which exhibited a positive correlation with more distal brain regions. Although there is a long way to go, such neurochemical-neurofunctional investigations could augment other diagnostic tests, and prove significant in evaluating neurological and psychiatric disorders featuring changing metabolite levels.
GABA signaling undergoes a series of developmental shifts that correspond to the state of maturity of the developing nervous system, and the integral role played by GABA in numerous aspects of its growth. GABA signaling initially entails excitatory, depolarizing currents in the immature nervous system before transitioning to the classic inhibitory, hyperpolarizing currents later on in development. The shift in conductance is a consequence of the altered expression patterns of chloride/cation transporters that induce the outflow of chloride ions from the neurons during early stages of development. These shifts underlie the events of early neurogenesis, namely, proliferation, migration, differentiation, neurite extension, and synaptic plasticity. The developmental shift in signaling from excitation to inhibition also coincides with the advent of post-natal sensory input processing. Deviations in this developmental program have been thought to play a role in certain neurodevelopmental disorders.
As GABA neurotransmission is crucial for normal function and its signaling is an essential component of diverse brain activities, GABA malfunction has been implicated in the etiology and pathophysiology of several neurological and psychiatric disorders, including epilepsy, anxiety disorders, stress, autism, schizophrenia, Parkinson’s disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS) - some of which are elaborated on below.
Moreover, GABA acts on peripheral non-neuronal tissue, and impaired functioning is associated with various disorders including, and not limited to hypertension and diabetes. GABA balance is considered beneficial for health, and it is touted for its anti-oxidant and antimicrobial properties. It is found naturally in foods such as green tea, soybean, and fermented foods such as kimchi and yogurt. Consequently, there is great interest in offering alternative, GABA based therapies in the form of GABA enriched foods or synthetic GABA compounds for various neurological and non-neurological conditions.
Synthesis and Metabolism of GABA
The neurotransmitter GABA is not synthesized de novo, but is derived from its precursor glutamate by the action of the rate-limiting enzyme, glutamic acid decarboxylase (GAD), and involves what is described as the 'GABA shunt' This shunt is part of the glutamate/GABA-glutamine cycle and connects the tricyclic acid (TCA) cycle to glutamate and GABA metabolism. The cycle entails the release of the neurotransmitters’ glutamate and GABA from pre-synaptic neurons, and the subsequent uptake and processing in neurons and astroglial cells. In the glial cells, the metabolic pathway invokes the mitochondrial TCA cycle and forms the shunt for synthesis of glutamine that is returned to the neurons for conversion to glutamate or GABA, depending on the identity of the neuron.
GABA released from the terminals into the synaptic cleft is not subject to enzymatic degradation and is predominantly cleared by diffusion or by uptake via specialized transporters. These transporters that belong to a neurotransmitter:sodium symporter family, recycle the neurotransmitter back into pre-synaptic neurons or transport it into astroglial cells, the latter representing a minor pathway for GABA replenishment. In humans, these transporters belong to what is referred to as the solute carrier 6 (SLC6) family, and encompass 20 (A1-A20) transporter proteins, that are differentially targeted to neurons or glial cells. Four groups of GABA transporters (GAT), that belong to the SLC6 family have been identified, GAT1-3 (SLC6A1, SLC6A13, SLC6A11), and betaine/GABA transporter 1 (BGT1/SLC6A12), the latter a focus of epilepsy. Although the transporters overlap in their distribution, GAT1 is considered predominantly neuronal, whereas GAT3 is principally glial.
Following the reuptake of GABA into the presynaptic neuron terminals, the neurotransmitter is repackaged into synaptic vesicles by vesicular GABA transporter (VGAT), ready to be rereleased. Another mode of enriching GABA in synaptic vesicles includes the uptake of glutamate into the terminals by excitatory amino acid transporters (EAAT1), the enzymatic conversion by GAD65 to GABA, and loading of the newly synthesized transmitter into synaptic vesicles, ready for release.
The astrocyte mode of recycling GABA involves the glutamate-glutamine cycle and is significantly associated with the subsequent inhibitory events of GABA interneurons, especially at active synapses. This pathway is ultimately purported to provide a substantial amount of GABA required at the synapse for maintaining sustained inhibitory activity. The astrocytic-neuronal - glutamate-glutamine-GABA cycle, dynamically links the excitatory glutamate pathway directly with the activity of the GABA neurosystem, ensuring the availability of loaded synaptic vesicles for release.
The recycled GABA, both in neurons and astrocytes, is catalytically converted to succinic semialdehyde by the enzyme GABA-transaminase (GABA-T), which is further processed into succinic acid by succinic semialdehyde dehydrogenase (SSADH). Succinic acid then enters the TCA cycle to form α-ketoglutarate, that is ultimately converted into the GABA precursor, glutamate. The transamination of GABA by GABA-T to subsequently form glutamate requires α-ketoglutarate to be in a position to accept the amino group generated from GABA processing. In this way the GABA supply is sustained, and adequate levels of the neurotransmitter are maintained for optimal function. The astroglial glutamate is catalyzed by glutamine synthetase (GS) to form glutamine that is released for uptake into the presynaptic terminals of GABAergic neurons. In GABA neurons, glutamine is converted to glutamate via the enzyme, phosphate-activated glutaminase (PAG), and subsequently glutamate is catalytically decarboxylated by GAD, in an irreversible reaction that generates GABA.
Glutamic acid decarboxylase, is an enzyme unique to GABAergic neurons and requires the cofactor pyridoxil phosphate (vitamin B6) for its catalytic activity. Two distinct isoforms of the enzyme, GAD65 and GAD67 have been discovered and are encoded by separate genes, exhibiting discrete functional properties, subcellular localization, and cofactor requirements. GAD65 is targeted to synaptic vesicles, being primarily deployed in neurotransmission, whereas cytoplasmic GAD67 is active and supplies GABA as a trophic factor during synaptogenesis, and injury protection.
Pathological states associated with auto-antibodies against GAD65 lower GABA levels, and have been linked with certain disorders, including diabetes mellitus type 1 (DM1) and certain neurological diseases. Patients with high anti-GAD65 antibodies suffering from motor and cognitive disorders manifest an incomplete and variable response to immuotherapy. These lines of investigation into anti-GAD65 syndromes and other pathologies linked to GABA metabolism need to be extended in order to gain a firm grip on the basis of these neurologic conditions, alleviate symptoms and provide relief to those suffering from these GABA-associated disorders.
The synthesis and metabolism of GABA regulates the levels of the transmitter available for signaling and GABA concentration has a dynamic impact on network activity and maintenance of excitatory and inhibitory homeostasis. The various enzymes, transporters, and proteins involved in these mechanisms have a powerful impact on the effectiveness of GABA function, and ultimately the functioning of the entire nervous system. In this regard, inadequacies in processing are implicated in various physiological, neurological, and psychiatric diseases, and are the targets of intense investigation for their therapeutic potential.
Interneurons, especially inhibitory interneurons make up approximately 20-30% of neurons in the adult neocortex, and their numbers vary with respect to particular cortical layers, regions, and species. Cortical GABAergic interneurons are critical for development, plasticity and normal function, and their complexity is increasingly compounded by their diversity. These inhibitory interneurons differ in many respects and are remarkable for their unique morphological and physiological features, intrinsic membrane properties, their engagement at the synaptic level, and their molecular identity.
Majority of these neurons have characteristic aspiny dendrites and smooth appearance attributable to inhibitory neurons. Decades of research along with the refinement of technical and analytical tools have elucidated the diversity of GABAergic interneurons. They are distinguished into particular types based on differences at the level of cell bodies, dendrites, and axons. Their cell bodies receive inhibitory and excitatory inputs and are integral components of neural circuits, serving to meter the excitatory drive and contribute to the appropriate synaptic output.
Arguably, it is the axon extent and arborization that is a more reliable identifier of a particular interneuron type than the pattern of its dendritic branching. Neocortical GABAergic neurons are ‘local circuit neurons’ that maintain a distinct columnar and laminar organization, with dendrites extending within and across columns, and with axons arborizing within the neocortex. They remain confined within the neocortical architecture, remaining true to their local aspect and refrain from elaborating neurites to sub-cortical regions. The different subtypes of GABA interneurons specialize in targeting different neuronal compartments to influence cell function. They form synapses at proximal and other aspects of dendrites, cell bodies, or on the axon initial segment. This targeting affords them the capacity to determinedly sculpt the spatiotemporal response generated by the target neuron and by extension, the whole assembly of neurons in a circuit. At present there are estimated to be approximately 50 types of GABAergic neurons identified in the cerebral cortex.
GABA interneurons exert their inhibition on principal pyramidal neurons, and in turn these neurons remain connected with other circuit principal neurons and interneurons in order to maintain E/I balance. These interactions and the activity contained in these circuits drives the local response and the communication between different brain regions. Disturbances of these finely tuned physiological patterns of brain activity has been linked to various disorders, including epilepsy and schizophrenia.
The inhibitory medium spiny neurons of the basal ganglia, are a GABAergic population of neurons that are uniquely positioned to influence motor function. The direct pathway from the cortex that loops through the basal ganglia serves to enhance motor activity by releasing GABA inhibition of the thalamocortical motor circuit. In contrast the indirect pathway serves to suppress motor activity by amplifying GABA inhibition of the thalamocortical motor circuit. Dysfunction in this system is implicated in the motor impairments observed in and not limited to Parkinson's and Huntington's diseases. In Huntington's disease, the GABAergic striatal medium spiny neurons are 'selectively' vulnerable to degeneration early on and contribute to the progressive motor and cognitive dysfunction.
Phenotypically the interneurons are differentiated into several subtypes that each concentrate different neuropeptides, calcium binding proteins, and receptors, including distinct parvalbumin (PV), somatostatin (STT), and ionotropic serotonin receptors (5-HT3A), vasoactive intestinal peptide (VIP) populations, that altogether account for 85 % - 100% of all interneurons in the cortex. Different interneuron types differentially target and release GABA and neuropeptides at specific post-synaptic sites and times in accordance with the requirements of behavior - fine tuning and tailoring their signals to the specific activity related to movement or alternatively, maintaining homeostasis  Recently the PV+, STT+, and VIP+ interneuronal populations in the mouse somatosensory cortex were mapped to determine the extent and type of cortical input received. These kinds of investigations reveal that different interneuronal populations are determined to leverage feedback and feedforward mechanisms in order to modulate the dynamics of their embedded local networks.
Based on decades of accumulated data on GABA interneurons the Petilla terminology was adopted in 2008 to enumerate these cell types owing to their morphological, physiological, and molecular characteristics. The organizing principle of this nomenclature takes into account the targeting by these interneurons of pyramidal cells or other interneurons. GABA interneurons are further distinguished by their terminations on different aspects of the pyramidal cells. Specifically, interneurons that form synapses at the axon initial segment and comprise the axo-axonic chandelier cells; those that connect with the soma, such as basket cells; and interneurons that target dendrites, either the dendritic shaft of neurons that go on to elaborate axons vertically, descending to the white matter, or those like the Martinotti cells whose axons ascend to the pia, and lastly the neurogliaform cells that preferentially target the dendritic spine.
The classification scheme further differentiates GABAergic interneurons based on their expression of certain molecular markers. These consist of the expression of PV, STT, 5-HT3A receptor/VIP, neuropeptide Y (NPY), and cholecystokinin (CCK). They are further categorized depending on whether each type colocalizes other peptides, and their complement of ion channels and receptors, structural and synapse related proteins, calcium binding proteins, transcription factors, among other distinguishing features. It is now evident that there is a distinct class of ionotropic serotonin 5-HT3A receptor expressing neocortical interneurons that based on their independent lineage do not overlap with the PV- or STT- interneuron populations. A significant subset, ~ 40%, of these interneurons accumulate VIP.
Recent studies conducted on transgenic mice coupled with optogenetic investigation of distinct, non-overlapping populations of PV, STT, and VIP expressing interneurons, have shed light on the contributions of these cells to neural circuits. Notably, the fast-spiking, PV-expressing interneurons such as the basket and chandelier cells, target the cell body and axon initial segment of other neurons, respectively. Additionally, their fast and sustained firing characteristics puts them in a dynamic position to impact the electrical activity of target neurons. Moreover, the interconnected cohort of PV-expressing interneurons have an equally strong impact on driving the synchronous activity of neurons. The signals from this select , PV+ subset of GABAergic interneurons influence the ensuing events considered consequential for cognitive function and behavior, and dysfunction in this process could lead to impairments associated with neurological and psychiatric diseases.
STT-expressing interneurons, including Martinotti cells project axons superficially in the cortex to influence the output related to sensory information processing. The axons of these interneurons target the apical dendrites of deeper, cortical layer 5, pyramidal neurons. Using fiber-optic recording methods, these layer 1, STT+ interneurons have been observed to inhibit the calcium spikes and bursting in the dendrites of the pyramidal neurons, a result also recorded in the hippocampus. The STT+ interneurons di-synaptically inhibit adjacent neurons, enabling them to powerfully control the activity of the micro-circuit that is responsible for the bottom-up encoding of sensory information. In the hippocampus, STT containing interneurons target the dendrites of CA1 pyramidal cells and their slow time course of action mediated by the α-5 GABAA receptors is suited to and influences the post-synaptic NMDA receptor activation kinetics. In this way the STT-expressing GABA interneurons control the synaptic integration and excitability of the post-synaptic pyramidal cells, proving to be an attractive site for synaptic plasticity. In contrast to their inhibitory effects, STT+ interneurons exert their influence on cortical microcircuitry and cortical information processing by disinhibiting the thalamic afferents to pyramidal neurons in layer 4 of the cortex, the critical input layer in sensory cortices that is important for information processing. The STT-expressing GABA interneurons have been classified into 5 types with distinct morphological and molecular features and laminar location in the human cerebral cortex. Of note is that in Alzheimer's disease, there is a selective loss of STT+ versus PVV+interneurons in the temporal lobe of the cortex, an area crucial for cognitive function and a predominant deficit seen in people with this disorder. This just underscores the significance of well balanced interneuronal circuits in maintaining optimal function.
The third class of GABAergic cortical interneurons with multiple morphologic features are superficially located, and express 5-HT3A receptor and VIP. They have a disinhibitory role of principally inhibiting STT- and a segment of PV-expressing interneurons. In sensory cortices, such as the visual cortex, the mutual, reciprocal antagonism exerted by VIP and STT interneurons contributes to the appropriate behavioral output, especially in response to weak stimuli. The VIP-expressing interneurons influence on local circuit activity, i.e., input and output of cortical pyramidal cells, is principally brought about by inhibiting the inhibitory STT and PV interneurons and is observed across many other regions of the cerebral cortex. This conserved feature has been demonstrated to be relevant for pyramidal cells response to reward-punishment, which constitutes a reinforcement signal and could be crucial for certain forms of learning. This subset of GABAergic-VIP interneurons plays an important role in different behavioral states, as it exerts inhibition and disinhibition on GABAergic and other neurons to modulate the activity of distinct circuits. STT+ and VIP+ interneurons in the somatosensory cortex have been found to be active early in the development of sensory processing, individually contributing to the activity that continues to mature into adulthood.
It is evident that the diversity of GABA interneurons is a salient and indispensable feature of the nervous system, making important contributions to cortical functioning and resultant behavioral states. At the individual level, these interneurons serve to temper the excitability and shape the response patterns of the pyramidal cell that can be tied to behavioral states. Zooming out to the network level, interneurons influence the formation of neural circuits that are crucial for propagating local activity and spreading excitation in the form of membrane oscillations. This architecture enables local interneurons to exert their actions at the network level, constantly refining cortical circuits, and providing a mechanism for synaptic plasticity and sensory processing. The above-described classification scheme lays bare the intriguingly complex connectivity and heterogeneity of these cell types, especially as there are about 50 identified GABA interneurons types as of now. Furthermore, investigations in humans of different GABA receptor subunit gene expression, combined with unique interneuron subtypes biomarkers, and receptor binding assays, demonstrate a correlation between certain subsets of inhibitory GABA interneurons and their receptors. Comprehensive, noninvasive studies, including but not limited to PET, optogenetic studies, (1H) MRS, of these kinds on humans shine a light on the identity of unique markers of diverse cortical GABA circuits, and how dysfunction at this level could have ramifications for neurological and psychiatric diseases.
GABA is critical for coordinating the activity of neurons at the individual and circuit level, and it exerts its inhibitory effects via two subtypes of receptors, namely GABAA and GABAB receptors.
Ionotropic GABAA Receptors
GABAA receptors are ligand-gated ion channels. The receptors are integral membrane proteins composed of 5 subunits that form a pore for regulating the passage of chloride into the cell (Figure 2). Alternative splicing of 20 gene products generates different types of subunits, i.e., six alpha (1-6), three beta (1-3), three gamma (1-3), three rho (1-3), and single delta, epsilon, pi, and theta subunits. Several classes of pharmacological agents bind to the receptor, and the combination of subunits forming the receptor define its functional properties. Majority of mature receptor isoforms in the mammalian nervous system are formed by three of these subtypes and are proposed to assume a combined stoichiometry of α1β2γ2 subunits. Furthermore, the GABAC ionotropic receptor isoform is composed of rho subunits and is considered to be part of GABAA family of receptors.
GABAA receptor subunits bear structural homology with other ligand-gated ion channels. Each subunit is composed of 4 transmembrane domains (TMD1-4), with GABA and psychoactive drugs such as benzodiazepine binding to sites on the extracellular N-terminal domain. The second TMD forms the pore for chloride ions, and the intracellular domain (ICD) represents sites for protein and other modulatory interactions. The long intracellular loop between TMD 3 and 4 binds to the scaffold protein gephyrin, that is the chief architect for organizing and maintaining the inhibitory post-synaptic density at the post-synaptic membrane. The receptor has distinct sites for binding neurosteroids and sedatives, such as barbiturates. The cell surface expression and turnover of GABAA receptors at synaptic sites is integral to robust inhibitory signals. Disruption of the processes that underlie the appropriate distribution of the receptors and intracellular recycling and turnover leads to perturbations of inhibitory neurotransmission. This perturbation in GABA inhibition alters the E/I balance and the resultant increase in excitatory tone is commonly linked with various disorders of the nervous system.
The diverse subunit composition of GABAA receptors confers differential sensitivity to distinct endogenous neurochemicals and pharmacological agents for modulating neuronal excitability. The subunit differences and distinct regional distribution patterns and cellular localization of the receptor enables it to have a profound influence on brain function. It further defines the post- or extra-synaptic location of the receptor that mediate phasic or tonic inhibition, respectively. Importantly, transient (< 1ms), phasic inhibition is a feature of classic, point-to-point neurotransmission at post-synaptic receptor sites that activate at higher (0.3-1mM) concentrations of the GABA in the synaptic cleft. This activity answers to benzodiazepines. Whereas the persistent, tonic form results from longer lasting modulation of inhibitory post-synaptic currents at extra-synaptic sites, requiring lower (μM) levels of the neurotransmitter to activate. The latter underlie more than just post-synaptic excitability but extend to oscillations at the network level, and are important for synaptic plasticity, neurogenesis, and cognitive functioning. Tonic GABAA receptor neurotransmission is the predominant form of GABA signaling in the brain and neurosteroids are known to be potent modulators of these high affinity extra-synaptic receptors. Neurosteroids are positive allosteric modulators (PAM) of extra-synaptic delta (δ)- subunit containing GABAA receptors. They enhance the tonic inhibition mediated by these receptors and serve as powerful anticonvulsants. Currently, research on surgically resected human cortical tissue from patients with various pathologies has confirmed the presence of GABAA mediated tonic inhibition.
The disruption in either phasic or tonic forms of inhibition is consequential for proper development and functioning and has been implicated in many neurological and psychiatric diseases. Pathological disease states and disorders such as epilepsy, stress, anxiety, schizophrenia, Parkinson’s disease, recovery following a stroke are all associated with dysfunction of GABAA receptor.
GABAA receptors have been shown to modulate the activity of excitatory cortical circuits by providing inhibitory inputs to influence the timing of spikes and the persistent activity of the network. There is considerable interest in further developing selective therapeutic agents based on the diversity of GABAA receptors and their impact for neuroprotection, maintenance of E/I balance, and ramifications for diseases.
Metabotropic GABAB Receptors
The metabotropic GABAB receptors belongs to the 7 transmembrane domain class C G protein-coupled receptor (GPCRs) superfamily. They play an important role in modulating neuronal and circuit excitability in the nervous system. These receptors are obligate heterodimers of GABAB1 (GB1) and GABAB2 (GB2) subunits, and heteromeric interactions between the two subunits is essential for the formation of a functional receptor (Figure 3). Each subunit has the extracellular Venus Flytrap (VFT) domain - characteristic of this class of receptors - wherein lies the ligand binding site. Whilst the GB1 subunits have been shown by radioligand binding and site-directed mutagenesis studies to bind with high affinity to GABA; allosteric compounds act on the GB2 subunit, which is crucial to intracellular coupling with G-proteins.
These receptors influence neuronal signaling by either inhibiting the release of neurotransmitters at presynaptic terminals, including as auto- or heteroreceptors on GABA or glutamate nerve terminals, respectively, or activating K+ channels at post-synaptic sites. GABAB receptors mediate slow and prolonged inhibition via intracellular activation of Gai/o protein cascades which include the inhibition of adenylate cyclase, activation of inwardly-rectifying K+ channels (GIRK), and inactivation of voltage-gated Ca2+ channels (Cav). The GABAB receptor inactivation of Cav channels at presynaptic terminals serves to interfere with neurotransmitter release, which is significantly consequential for neurotransmission. It follows that pre-synaptically located GABAB receptors inhibit glutamate release. Post-synaptic membrane excitability is altered by the enhanced conductivity of GIRK channels induced by GABAB receptor activation. The subsequent K+ efflux through these channels, results in membrane hyperpolarization that underlies the slow and prolonged inhibitory post-synaptic potentials (IPSP) attributed to GABA signaling. Tonic activation of extra-synaptic GABAB receptors by other interneurons in the vicinity occurs in response to GABA spillover, i.e., escaping of the the neurotransmitter from the immediate post-synaptic site. This activation of the GABAB receptors is thought to contribute the important inhibitory component of hippocampal rhythmic activity. In contrast to others GPCRs, these receptors remain stable at the plasma membrane, resisting internalization even after agonist exposure. The absence of endocytosis of GABAB receptors until their subsequent degradation in the natural course of events, correlates with lack of arrestin recruitment and with enhanced stability after cAMP- mediated PKA phosphorylation. Their membrane stability is consistent with the importance role they have in moderating neuronal excitability, and contributing to rhythmic activity. Interestingly, it is glutamate and not GABA that has been tied to the turnover of GABAB receptors, as it decreases the number of receptors at the plasma membrane and initiates trafficking through the lysosomal pathway.
GABAB receptors signal transduction is augmented by interactions with other proteins, such as scaffold, trafficking proteins, enzymes, ion channels, GPCRs, including glutamate receptors. The GABAB receptors regulates the ionotropic glutamate NMDA receptor (NMDAR) function indirectly by controlling glutamate release from pre-synaptic terminals and directly by influencing NMDAR calcium signaling at post-synaptic sites. The post-synaptic NMDAR calcium influx, important for membrane excitability, is inhibited by GABAB receptors, however the glutamate receptor retains the ability to respond to NMDA with synaptic currents. The hyperpolarization and diminished current attributed to the activity of GIRK channels, is conducive to maintaining the Mg2+ block of NMDAR channels. The GABAB receptors also inhibit the activity of PKA, which is thought to be important for NMDAR calcium signaling. Furthermore, as mentioned above, GABAB receptors also function to attenuate the presynaptic release of glutamate by suppressing calcium entry directly through voltage-gated calcium channels. The activity of and calcium signaling by NMDARs is essential for neuronal excitability, neuroplasticity, and dendritic spine remodeling. Therefore, widespread prevalence of GABAB receptors has broad implications for calcium signaling in the nervous system.
Dysfunction of NMDARs is implicated in neuropathologies and neuropsychiatric diseases, such as pain, autism, and schizophrenia. GABAB receptor agents have been shown to reverse certain deficits of the glutamate receptor, and thereby could be suitable therapeutic targets for treating NMDAR-dysfunction related disorders. Additionally, GABAB receptors interact with ionotropic AMPA receptors, providing another suitable target for these agents. The activation of GABAB receptors serves to inhibit the persistent activity of cortical circuits. The excitatory-inhibitory E/I balance in the nervous system is mediated by both these neurotransmitters, and imbalances contributing to diseases in humans, like schizophrenia, are being studied in post-mortem tissue for the development of biomarkers.
The GABARs form complexs with metabotropic glutamate receptors (mGluRs) at the plasma membrane, and this higher-order GPCR complex is functionally regulated in a manner distinct from the regulation of the individual receptor unit. The two receptors are known to be colocalized at peri-synaptic sites of dendritic spines, which enables them to interact, and is conducive to cross-talk between them. These effects have a significant impact on neurotransmitter release, neuronal and circuit excitability, synaptic plasticity, neurogenesis. GABAB receptors interact with the glutamate system in the hippocampus to influence spatial learning and cognition, functioning that is impaired in certain psychiatric disorders.
The various mechanisms at play alter the pharmacology and functioning of GABAB receptors and offer up a unique palette of sites for receptor modulation and drug development for therapeutic purposes. Currently, the only GABAB receptor compound in use is the agonist baclofen, which acts at both pre- and post-synaptic sites in the central nervous system. It is approved for use as an antispastic agent and in treatment of multiple sclerosis and spinal cord injury, and is used off-label as a muscle relaxant.
Its is evident that the proper functioning of the brain and nervous system on the whole relies on balanced E/I signaling. Dysregulation at the levels of GABA and glutamate is considered central to the etiology of various neurological and neuropsychiatric disorders. Integrating the the realm of imaging, which is continually evolving, with more refined technologies such as proton magnetic resonance spectrography (1H MRS) that samples neurotransmitter concentrations in vivo, are proving to be exciting and invaluable resources for providing insights into the neuroanatomical and neurochemical correlates of brain dysfunction. These applications combined with behavioral, neurophysiological, and molecular approaches is adding to our understanding of the very reasons for these complex disorders, and potentially opening up interventional approaches that have previously not been identified. Additionally, more potent and selective drugs are being recruited for their novel and strategic therapeutic potential to treat disorders related to GABA dysfunction. Impairment in GABA signaling is crucially implicated in many disorders, as discussed below.
GABA neurotransmission is critical for cortical synaptic plasticity and maintainance of E/I balance as it impacts the internal cortical circuitry and output of its principal, pyramidal neurons. Depression has been associated with a deficit of GABA functioning in the brain at multiple levels, from reduced concentrations of the neurotransmitter to structural and functional alterations of GABAA receptors, and the ability of available anti-depressants acting via the GABAergic system to mitigate depression. The rapid effects of anti-depressants that target either monoamines, glutamate or acetylcholine signaling in order to ameliorate depressive symptoms are though to act by altering localized GABA activity. In this regard, the NMDA receptor subunit GluN2B on GABA interneurons in the medial prefrontal cortex, appears to be the preliminary site of action of the rapid-acting antidepressant ketamine. GABAA receptors are of particular interest in the treatment for depression, and the neurosteroid allopregnanolone along with other positive allosteric modulators (PAM) of the receptor are being deployed for treatment. The extra-synaptic GABAA receptors located on pyramidal cells in cortical and subcortical hippocampal sites - regions implicated in depressive and anxious states, respectively - are targets of GABAA-receptor selective positive allosteric modulator antidepressants (GASPAMA).
There have been reports from multimodal studies contradicting the GABA-deficit hypothesis, however these studies have different paradigms, cohorts and drug regimes that preclude any definite synthesis of results. GABA concentrations have been found to be unchanged in patients at risk of developing major depressive disorder (MDD) suggesting they cannot be considered a trait marker for the eventual development of the disorder. The regions evaluated in patients at risk of developing major depressive disorder (MDD) using combined investigational approaches, including 1H MRS, have comprised the prefrontal and parito-occipital cortex, preoptic area, and other regions of the brain.
It is clear that despite the challenges, the novel GABA agents currently in use or in the pipeline to treat depression, are based on a better understanding of GABA and its crucial role in neurotransmission, and are proving to be beneficial in management of depression.
Stress, Fear, and Anxiety
Low levels of GABA are associated with stress, fear, and anxiety. The amygdala in the temporal lobe is a structure central to the processing of unpleasant, stressful, and fearful stimuli. GABA neurons in the amygdala are key components in maintaining the stability of excitatory and inhibitory neurotransmission. The amygdala is composed of numerous nuclei, and amongst its subdivisions is the basolateral amygdala (BLA), a structure crucial for processing emotional and motivational states, and central amygdala (CeA), that is entirely gabaergic and critical for processing of stressful and fearful stimuli. A comparatively modest set of GABA interneurons in the BLA balances out the glutamatergic excitation, and this group provides input to the GABA interneurons of the CeA that exit the amygdala. GABA neurons in the amygdala are influenced by a diversity of afferent neurotransmitter systems, arriving from both cortical and subcortical regions that serve to facilitate GABA signaling. GABA interneurons are uniquely placed to efficiently influence the circuitry and function of the amygdala, and importantly to effectively contribute to the behavioral responses in stressful circumstances.
Disruption of BLA GABAergic interneurons, including cellular loss, reduction in the activity of the GABA synthesizing enzyme (GAD65/67), or dysfunction related to the activity of GABAA receptors, undermines the E/I balance and underlies states of hyperexcitability. This excitability presents as anxiety and other behavioral and emotional disturbances, including seizures. Dysregulation of these neurons and the accompanying anxiety can have longer term consequences for the development of psychiatric post-traumatic stress disorders (PTSD), and neurodegenerative diseases such as Alzheimer’s disease.
Furthermore, GABA has an inhibitory effect on the hypothalamic release of corticotropin-releasing hormone (CRF) and vasopressin that are involved in the activation of the stress-related, hypothalamo-pituitary adrenal (HPA) axis. Reduced GABA in pathological states removes the inhibition that keeps the HPA system in check. Subsequently, the over-activity associated with the HPA axis is associated with, and not limited to stress and anxiety.
Treatment for stress disorders include benzodiazepines, which are limited in their utility based on the delineation of the underlying physiological determinant of the dysfunctional response, a limitation which would obviate their effectiveness. Impairments such an underlying loss of BLA GABAergic interneurons or GAD activity responsible for bringing about the dysfunctional stress response, would prove refractory to treatment with benzodiazepines.
The neural substrates of working memory, are underpinned by activity of both glutamate and GABA acting in concert, and presents as gamma oscillations in the dorsolateral prefrontal cortex (DLPFC). Working memory and other cognitive deficits are a defining, negative feature of schizophrenia. Alterations in GABA transmission in the supragranular cortical layers, especially the circuits involving the deep layer 3/4 PV+ neurons, and the more superficial layer 2/3 and SST+ neurons that form synapses with layer 3 pyramidal cells, are responsible for these cognitive deficits. Oscillatory activity of DLPFC pyramidal neurons is synchronized by the inhibitory synaptic input of GABA interneurons - pyramidal interneuron network gamma (PING) model. These gamma oscillations (30-80Hz) that underpin working memory are observed to be compromised in patients with schizophrenia. Thus, the paucity of cortical GABA signaling contributes to this negative symptom of schizophrenia, and noninvasive tests could identify aberrant cortical gamma activity and serve as a biomarker for schizophrenia.
Certain subpopulations of GABA interneurons, like PV+ basket cells, may be selectively vulnerable in schizophrenia. Postmortem tissue analysis has consistently shown a decrease in the mRNA levels of the enzyme GAD67 in the presynaptic terminals of especially PV+ and SST+ GABA interneurons, pointing to a reduction in the synthesis of GABA and robustness of neurotransmission. In accordance with this, the activity of the post-synaptic GABAA receptors targeted by these interneurons is also weakened due to lowered alpha subunit levels. Apart from this, lower levels of SST+ neurons in the DLPFC are also observed and could contribute to the microcircuits that underlie the oscillatory activity underpinning the deficits in the working memory of schizophrenia patients. Agents that selectively and positively modulate the activity of these receptors have been shown to positively impact cortical activity and task performance in patients with schizophrenia.
Multimodal studies, combining 1H MRS to determine the concentration of GABA, have revealed regional reductions in GABA in the frontal and occipital cortex, and basal ganglia. These studies on their own do not indicate a causal role of GABA in schizophrenia, but suggest a perturbation in E/I balance - a subject of many current investigations.
Epilepsy bestows an enormous burden of disease to the world, afflicting 50 million people globally and 3.4 million people in the US alone. Temporal lobe epilepsy is the most common form of partial epilepsy, accounting for 60% of adult cases, and is characterized by recurrent and unprovoked focal seizures of the temporal lobe. GABA neurotransmission is held as a counterbalance to the excitation brought about by glutamate signaling, and both are tasked with maintaining E/I homeostasis. Valproate, a broad spectrum drug in wide use to treat epilepsy is believed to act mechanistically by potentiating GABA inhibition and reducing glutamate/NMDA receptor mediated excitation. The consequences of GABA signaling in maintaining E/I balance is more significant and richer than just its actions assigned to inhibition, and dysregulation of the system has implications for generation of epileptic seizures. The diversity and dysfunction of GABA interneurons at the network, electrophysiological, subcellular, and molecular levels contributes to the complex nature of epileptogenesis. However, GABA signaling has recently been revealed to both promote and suppress epileptic seizures. Additionally, astroglial cells play a critical role in the metabolic changes associated with the E/I balance of GABA and glutamate signaling. Long-lasting impairment of these cells as a consequence of epileptogenic changes could lead to alterations in the astrocyte-neuron network and could perturb the E/I homeostasis.
Disrupted GABA inhibition perpetuates and intensifies the self-sustaining epileptic seizures, with attendant behavioral and neurological disturbances. GABAA receptors are considered to be mainly responsible for these seizures, and positive allosteric modulators (PAM), benzodiazepines, that target the γ2 subunits of these receptors are deployed as the first line of treatment. These receptors mediate the phasic, fast inhibition in response to high GABA concentrations attributed to synaptic GABAA receptors. Cationic ion channel transporters such as the K+-Cl- cotransporter isoform 2, KCC2, and Na+-K+-2Cl- cotransporter isoform 1, NKCC1 are critical for maintaining the ionic gradients that define the flow of ion currents through the receptor ion channels. These ion channels and receptors are subject to immediate and pathological seizure-related post-translational changes, and this has an impact on their availability and function, and consequentially this 'ion plasticity' is responsible for changes in membrane excitability. These rapid changes at the membrane level are also consequential for the time-limited responsiveness to benzodiazepines, as they are rendered ineffective in treatment of prolonged seizures.
Following precipitating events of epileptogeneisis, such as stroke, traumatic brain injury (TBI), seizures, hypoxia, transcriptional activity alters the levels of receptor subunits expressed. These transcriptional changes brought about by growth factors such as BDNF and other transcription factors like CREB, alters the targeting of GABAA receptors and changes the levels of post- and extra-synaptic receptors, resulting in a shift toward tonic signaling. These changes in subunit composition renders the receptor less sensitive to benzodiazepines, and may be a factor that should be considered in treating epilepsy. Tonic inhibition is preserved with the changes brought about by epileptic seizures, and it serves to constrains excitatory network activity. This mode of GABAA receptor signaling may well represent targets for drug interventions in the treatment of epilepsy. Of note is the neurosteroid sensitivity of extra-synaptic GABAA receptors. Eplileptogenesis has numerous causes, symptoms, prognosis and treatment, and as such has certain common, clearly defining and more individually unique features.
GABA signaling and plasticity are relevant to the development of neuropathic and other painful conditions. GABA neurons and GABA receptors are found in all regions of the brain and spinal cord essential for mediating the perceiving pain. Under noxious circumstances disturbances in GABA neurotransmission disrupts the glutamate/GABA mediated E/I homeostasis. It has long be considered that central sensitization of excitatory signals in the dorsal horn of the spinal cord, that receives inputs from the peripheral sensory receptors of the primary afferent fibers, is important for pain processing. However, it is abundantly clear that deficits in inhibitory GABA signaling is crucial for the generation of neuropathic and other pain, and that agents that activate GABAA receptors can be leveraged for treatment of these pathological conditions. Pain- and damage-related alterations in GABA function, extend from paucity of neurotransmitter synthesis to neuronal apoptosis in the dorsal horn, some portion of the latter presumably from excitotoxic insult. Plasticity of GABA interneurons is observed along the neuraxis, in the descending nociceptive pathways, from the receptors in the periphery to the dorsal horn of the spinal cord, and higher, central pain processing centers. The plasticity attributed to GABA interneurons expands its repertoire of contributions to neural circuits, making it amenable to incorporate an effective and adaptive response to healthy physiological demands and those placed by noxious stimuli.
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