Gamma-aminobutyric Acid Signaling Research Articles

MR Spectroscopy Assessment of Daily Variations of GABA Levels within the Parietal Lobe and Anterior Cingulate Gyrus Regions of Healthy Young Adults.

The changes that occur in the gamma-aminobutyric acid (GABA) levels within specific brain regions throughout the day are less clear. To evaluate the daily fluctuations of GABA levels within the parietal lobe (PL) and anterior cingulate gyrus (ACC) regions and explore their association with melatonin (MT) levels, heart rate (HR), and blood pressure. Prospective. 26 healthy young adults (15 males and 11 females aged 22-27 years). 3.0T, T1-weighted imaging, Mescher-Garwood point resolved spectroscopy (MEGA-PRESS) sequence. The acquired GABA signal contained the overlapping signals of macromolecules and homocarnosine, hence expressed as GABA+. The creatine (Cr) signal was applied as an endogenous reference. The GABA+, GABA+/Cr were measured at six different time points (1:00, 5:00, 9:00, 13:00, 17:00, and 21:00 hours) using MEGA-PRESS. The blood pressure, HR and sputum MT levels, were also acquired. The one-way repeated-measures analysis of variance (ANOVA) was used to evaluate the GABA, blood pressure, HR, and MT levels throughout the day. A general linear model was used to find the correlation between GABA and blood pressure, HR, and MT. P < 0.05 was statistically significant. Significant variations in GABA+/Cr and GABA+ levels were observed throughout the day within the PL region. The lowest levels were recorded at 9:00 hour (GABA+/Cr: 0.100 ± 0.003，GABA+:1.877 ± 0.051 i.u) and the highest levels were recorded at 21:00 hour (GABA+/Cr: 0.115 ± 0.003, GABA+:2.122 ± 0.052 i.u). The MT levels were positively correlated with GABA+/Cr (r = 0.301) and GABA+ (r = 0.312) within the ACC region. GABA+/Cr and GABA+ in ACC are positively correlated with MT. GABA levels in the PL have diurnal differences. These findings may indicate that the body's GABA level change in response to the light-dark cycle. 1 TECHNICAL EFFICACY: Stage 2.

Perinatal exposure to bisphenol A impairs cognitive function via the gamma-aminobutyric acid signaling pathway in male rat offspring.

Bisphenol A (BPA) is a common synthetic endocrine disruptor that can be utilized in the fabrication of materials such as polycarbonates and epoxy resins. Numerous studies have linked BPA to learning and memory problems, although the precise mechanism remains unknown. Gamma-aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in the vertebrate central nervous system, and it is intimately related to learning and memory. This study aims to evaluate whether altered cognitive behavior involves the GABA signaling pathway in male offspring of rats exposed to BPA during the prenatal and early postnatal periods. Pregnant rats were orally given BPA (0, 0.04, 0.4, and 4 mg/kg body weight (BW)/day) from the first day of pregnancy to the 21st day of breastfeeding. Three-week-old male rat offspring were selected for an open-field experiment and a new object recognition experiment to evaluate the effect of BPA exposure on cognitive behavior. Furthermore, the role of GABA signaling markers in the cognition affected by BPA was investigated at the molecular level using western blotting and real-time polymerase chain reaction (RT-PCR). The research demonstrated that BPA exposure impacted the behavior and memory of male rat offspring and elevated the expression of glutamic acid decarboxylase 67 (GAD67), GABA type A receptors subunit (GABAARα1), and GABA vesicle transporter (VGAT) in the hippocampus while decreasing the expression levels of GABA transaminase (GABA-T) and GABA transporter 1 (GAT-1). These findings indicate that the alteration in the expression of GABA signaling molecules may be one of the molecular mechanisms by which perinatal exposure to BPA leads to decreased learning and memory in male rat offspring.

The hepatic GABAergic system promotes liver macrophage M2 polarization and mediates HBV replication in mice

Macrophages display functional phenotypic plasticity. Hepatitis B virus (HBV) infection induces polarizations of liver macrophages either to M1-like pro-inflammatory phenotype or to M2-like anti-inflammatory phenotype. Gamma-aminobutyric acid (GABA) signaling exists in various non-neuronal cells including hepatocytes and some immune cells. Here we report that macrophages express functional GABAergic signaling components and activation of type A GABA receptors (GABAARs) promotes M2-polarization thus advancing HBV replication. Notably, intraperitoneal injection of GABA or the GABAAR agonist muscimol increased HBV replication in HBV-carrier mice that were generated by hydrodynamical injection of adeno-associated virus/HBV1.2 plasmids (pAAV/HBV1.2). The GABA-augmented HBV replication in HBV-carrier mice was significantly reduced by the GABAAR inhibitor picrotoxin although picrotoxin had no significant effect on serum HBsAg levels in control HBV-carrier mice. Depletion of liver macrophages by liposomal clodronate treatment also significantly reduced the GABA-augmented HBV replication. Yet adoptive transfer of liver macrophages isolated from GABA-treated donor HBV-carrier mice into the liposomal clodronate-pretreated recipient HBV-carrier mice restored HBV replication. Moreover, GABA or muscimol treatment increased the expression of “M2” cytokines in macrophages, but had no direct effect on HBV replication in the HepG2.2.15 cells, HBV1.3-transfected Huh7, HepG2, or HepaRG cells, or HBV-infected Huh7-NTCP cells. Taken together, these results suggest that increasing GABA signaling in the liver promotes HBV replication in HBV-carrier mice by suppressing the immunity of liver macrophages, but not by increasing the susceptibility of hepatocytes to HBV infection. Our study shows that a previously unknown GABAergic system in liver macrophage has an essential role in HBV replication.

Lipopolysaccharide augments microglial GABA uptake by increasing GABA transporter-1 trafficking and bestrophin-1 expression.

Gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the brain, affects numerous immune cell functions. Microglia, the brain's resident innate immune cells, regulate GABA signaling through GABA receptors and express the complete GABAergic machinery for GABA synthesis, uptake, and release. Here, the use of primary microglial cell cultures and ex vivo brain tissue sections allowed for demonstrating that treatment with lipopolysaccharide (LPS) increased microglial GABA uptake as well as GABA transporter (GAT)-1 trafficking. This effect was not entirely abolished by treatment with GAT inhibitors (GAT-Is). Notably, LPS also induced microglial upregulation of bestrophin-1 (BEST-1), a Ca2+ -activated Cl- channel permeable to GABA. Combined administration of GAT-Is and a BEST-1 inhibitor completely abolished LPS-induced microglial GABA uptake. Interestingly, increased microglial GAT-1 membrane turnover via syntaxin 1A was detected in LPS-treated cultures after BEST-1 blockade. Altogether, these findings provided evidence for a novel mechanism through which LPS may trigger the inflammatory response by directly altering microglial GABA clearance and identified the GAT-1/BEST-1 interplay as a potential novel mechanism involved in brain inflammation.

Insights into the leveraging of GABAergic signaling in cancer therapy.

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain of adult mammals. Several studies have demonstrated that the GABAergic system may regulate tumor development via GABA receptors, downstream cyclic adenosine monophosphate (cAMP) pathway, epithelial growth factor receptor (EGFR) pathway, AKT pathway, mitogen-activated protein kinase (MAPK) or extracellular signal-related kinases (ERK) pathway, and matrix metalloproteinase (MMP) pathway, although the exact mechanism is unclear. Pioneering studies reported that GABA signaling exists and functions in the cancer microenvironment and has an immunosuppressive effect that contributes to metastasis and colonization. This article reviews the molecular structures and biological functions of GABAergic components correlated with carcinogenesis, the mechanisms underlying GABAergic signaling that manipulate the proliferation and invasion of cancer cells, and the potential GABA receptor agonists and antagonists for cancer therapy. These molecules may provide an avenue for the development of specific pharmacological components to prevent the growth and metastasis of various cancers.

Gamma-Aminobutyric Acid Signaling in Damage Response, Metabolism, and Disease

Gamma-aminobutyric acid (GABA) plays a crucial role in signal transduction and can function as a neurotransmitter. Although many studies have been conducted on GABA in brain biology, the cellular function and physiological relevance of GABA in other metabolic organs remain unclear. Here, we will discuss recent advances in understanding GABA metabolism with a focus on its biosynthesis and cellular functions in other organs. The mechanisms of GABA in liver biology and disease have revealed new ways to link the biosynthesis of GABA to its cellular function. By reviewing what is known about the distinct effects of GABA and GABA-mediated metabolites in physiological pathways, we provide a framework for understanding newly identified targets regulating the damage response, with implications for ameliorating metabolic diseases. With this review, we suggest that further research is necessary to develop GABA's beneficial and toxic effects on metabolic disease progression.

Angiotensin-converting enzyme 2 improves hepatic insulin resistance by regulating GABAergic signaling in the liver

The angiotensin-converting enzyme 2 (ACE2)/angiotensin 1-7/MAS axis and the gamma-aminobutyric acid (GABA)ergic signaling system have both been shown to have the dual potential to improve insulin resistance (IR) and hepatic steatosis associated with obesity in the liver. Recent studies have demonstrated that ACE2 can regulate the GABA signal in various tissues. Notwithstanding this evidence, the functional relationship between ACE2 and GABA signal in the liver under IR remains elusive. Here, we used high-fat diet-induced models of IR in C57BL/6 mice as well as ACE2KO and adeno-associated virus-mediated ACE2 overexpression mouse models to address this knowledge gap. Our analysis showed that glutamate decarboxylase (GAD)67/GABA signaling was weakened in the liver during IR, whereas the expression of GAD67 and GABA decreased significantly in ACE2KO mice. Furthermore, exogenous administration of angiotensin 1-7 and adeno-associated virus- or lentivirus-mediated overexpression of ACE2 significantly increased hepatic GABA signaling in models of IR both invivo and invitro. We found that this treatment prevented lipid accumulation and promoted fatty acid β oxidation in hepatocytes as well as inhibited the expression of gluconeogenesis- and inflammation-related genes, which could be reversed by allylglycine, a specific GAD67 inhibitor. Collectively, our findings show that signaling via the ACE2/A1-7/MAS axis can improve hepatic IR by regulating hepatic GABA signaling. We propose that this research might indicate a potential strategy for the management of diabetes.

Elevated GABA level in the precuneus and its association with pain intensity in patients with postherpetic neuralgia: An initial proton magnetic resonance spectroscopy study

PurposeThis study aimed to explore the changes in gamma-aminobutyric acid (GABA) and glutamate (Glu) levels, and their correlations with clinical indicators in patients with postherpetic neuralgia (PHN). MethodsA totally of 22 PHN patients and 21 sex-, age-, and education-matched healthy controls (HCs) underwent proton magnetic resonance spectroscopy scanning. The spectral data of GABA in the precuneus was obtained by Mescher-Garwood point-resolved spectroscopy, whereas the spectral data of Glu, total N-acetyl-l-aspartic acid (tNAA) and total choline (tCho) were obtained by point-resolved spectroscopy. The pain intensity of PHN was assessed by numeric rating scales (NRS). The edited GABA signal was displayed as GABA+ due to overlapping macromolecules and homocarnosine signals. Total creatine (tCr) level in individual was used as an endogenous reference. The neurometabolites levels of PHN patients were compared with those of healthy individuals and the correlations with clinical variables (pain duration and intensity) were analyzed. ResultsPHN patients had higher GABA+/tCr levels in the precuneus than HCs (P = 0.009), with no significant differences in the levels of Glu/ tCr, tNAA/ tCr and tCho/ tCr (all P > 0.05). The GABA+/ tCr levels were positively correlated with the NRS scores of the PHN patients (r = 0.473, P = 0.030). ConclusionIncreased GABA+/tCr levels in the precuneus and their association with pain intensity of PHN patients suggested a key role of the abnormalities of regional GABAergic neurons in the pathophysiological mechanisms of pain in PHN.

Low Dopamine D2 Receptor Expression Drives Gene Networks Related to GABA, cAMP, Growth and Neuroinflammation in Striatal Indirect Pathway Neurons

BackgroundA salient effect of addictive drugs is to hijack the dopamine reward system, an evolutionarily conserved driver of goal-directed behavior and learning. Reduced dopamine type 2 receptor availability in the striatum is an important pathophysiological mechanism for addiction that is both consequential and causal for other molecular, cellular, and neuronal network differences etiologic for this disorder. Here, we sought to identify gene expression changes attributable to innate low expression of the Drd2 gene in the striatum and specific to striatal indirect medium spiny neurons (iMSNs). MethodsCre-conditional, translating ribosome affinity purification (TRAP) was used to purify and analyze the translatome (ribosome-bound messenger RNA) of iMSNs from mice with low/heterozygous or wild-type Drd2 expression in iMSNs. Complementary electrophysiological recordings and gene expression analysis of postmortem brain tissue from human cocaine users were performed. ResultsInnate low expression of Drd2 in iMSNs led to differential expression of genes involved in GABA (gamma-aminobutyric acid) and cAMP (cyclic adenosine monophosphate) signaling, neural growth, lipid metabolism, neural excitability, and inflammation. Creb1 was identified as a likely upstream regulator, among others. In human brain, expression of FXYD2, a modulatory subunit of the Na/K pump, was negatively correlated with DRD2 messenger RNA expression. In iMSN-TRAP-Drd2HET mice, increased Cartpt and reduced S100a10 (p11) expression recapitulated previous observations in cocaine paradigms. Electrophysiology experiments supported a higher GABA tone in iMSN-Drd2HET mice. ConclusionsThis study provides strong molecular evidence that, in addiction, inhibition by the indirect pathway is constitutively enhanced through neural growth and increased GABA signaling.

Diazepam binding inhibitor governs neurogenesis of excitatory and inhibitory neurons during embryonic development via GABA signaling

Of the neurotransmitters that influence neurogenesis, gamma-aminobutyric acid (GABA) plays an outstanding role, and GABA receptors support non-synaptic signaling in progenitors and migrating neurons. Here, we report that expression levels of diazepam binding inhibitor (DBI), an endozepine that modulates GABA signaling, regulate embryonic neurogenesis, affecting the long-term outcome regarding the number of neurons in the postnatal mouse brain. We demonstrate that DBI is highly expressed in radial glia and intermediate progenitor cells in the germinal zones of the embryonic mouse brain that give rise to excitatory and inhibitory cells. The mechanism by which DBI controls neurogenesis involves its action as a negative allosteric modulator of GABA-induced currents on progenitor cells that express GABAA receptors containing γ2 subunits. DBI's modulatory effect parallels that of GABAA-receptor-mediating signaling in these cells in the proliferative areas, reflecting the tight control that DBI exerts on embryonic neurogenesis.

The effects of ruminant milk treatments on hippocampal, striatal, and prefrontal cortex gene expression in pigs as a model for the human infant.

While infant formula is usually bovine milk-based, interest in other ruminant milk-based formulas is growing. However, whether different ruminant milk treatments with varying nutrient compositions influence the infant’s brain development remains unknown. The aim was to determine the effects of consuming bovine, caprine, or ovine milk on brain gene expression in the early postnatal period using a pig model of the human infant. Starting at postnatal day 7 or 8, pigs were exclusively fed bovine, ovine, or caprine milk for 15 days. The mRNA abundance of 77 genes in the prefrontal cortex, hippocampus, and striatum regions was measured at postnatal day 21 or 22 using NanoString. The expression level of two hippocampal and nine striatal genes was most affected by milk treatments, particularly ovine milk. These modulatory genes are involved in glutamate, gamma-aminobutyric acid, serotonin, adrenaline and neurotrophin signaling and the synaptic vesicle cycle. The expression level of genes involved in gamma-aminobutyric acid signaling was associated with pigs’ lactose intake. In contrast, milk treatments did not affect the mRNA abundance of the genes in the prefrontal cortex. This study provides the first evidence of the association of different ruminant milk treatments with brain gene expression related to cognitive function in the first 3 months of postnatal life.

Quantifying GABA in Addiction: A Review of Proton Magnetic Resonance Spectroscopy Studies.

Gamma-aminobutyric acid (GABA) signaling plays a crucial role in drug reward and the development of addiction. Historically, GABA neurochemistry in humans has been difficult to study due to methodological limitations. In recent years, proton magnetic resonance spectroscopy (1H-MRS, MRS) has emerged as a non-invasive imaging technique that can detect and quantify human brain metabolites in vivo. Novel sequencing and spectral editing methods have since been developed to allow for quantification of GABA. This review outlines the clinical research utilization of 1H-MRS in understanding GABA neurochemistry in addiction and summarizes current literature that reports GABA measurements by MRS in addiction. Research on alcohol, nicotine, cocaine, and cannabis addiction all suggest medications that modulate GABA signaling may be effective in reducing withdrawal, craving, and other addictive behaviors. Thus, we discuss how improvements in current MRS techniques and design can optimize GABA quantification in future studies and explore how monitoring changes to brain GABA could help identify risk factors, improve treatment efficacy, further characterize the nature of addiction, and provide crucial insights for future pharmacological development.

The potential contribution of the WRKY53 transcription factor, gamma-aminobutyric acid (GABA) transaminase, and histone deacetylase in regulating growth, organogenesis, photosynthesis, and transcriptional responses of tomato to different light-emitting diodes (LEDs).

Impressive progress in developing light-emitting diodes (LEDs) offers a new dimension for meeting agricultural and biological expectations. The present study addresses how tomato (Solanum lycopersicum) seedlings respond to the different spectral qualities of LEDs (white, red, blue, and blue + red). The light treatments in a wavelength-dependent manner contributed to the variations in biomass accumulation, morphology, and organogenesis pattern. Light quality epigenetically contributed to the transcriptional regulation of the histone deacetylase (HDA3) gene. The expression of WRKY53 transcription factor and gamma-aminobutyric acid transaminase (GABA-TP1) genes displayed a similar upward trend in response to the blue wavelength. On the contrary, the sole red light downregulated the WRKY53 and GABA-TP1 genes. The blue irradiation was associated with the upregulation in the glycolate oxidase (GLO2) and ribulose-1,5-bisphosphate carboxylase‑oxygenase large subunit (rbcL) genes, while the red wavelength down-regulated the GLO2 and rbcL genes. Moreover, rbcL statistically correlated with GLO2, referring to the balanced regulation of photorespiration and the Calvin cycle. The blue wavelengths were more capable of improving the concentrations of photosynthetic pigments and proline. The seedlings grown under the white LEDs displayed the maximum activity of the catalase enzyme. The cultivation of tomato seedlings under the blue lights enhanced the activities of the superoxide dismutase and ascorbate peroxidase enzymes. The light treatments were associated with the variation in the nutritional status of K+ and Ca2+ in both leaves and roots. The presented findings and inferences support the potential contribution of WRKY53, HDA3, and GABA signaling in modulating plant responses to light quality.

Decreased Brain GABA Levels in Patients with Migraine Without Aura: An Exploratory Proton Magnetic Resonance Spectroscopy Study

Increasing neurophysiological studies had revealed that regional excitation-inhibition imbalance in the brain played a key role in the pathogenesis of migraine. This study aimed to explore the alterations in gamma-aminobutyric acid (GABA) and glutamate/glutamine complex (Glx) levels in the anterior cingulate gyrus (ACC) and medial prefrontal lobe (mPFC) of patients with migraine without aura (MWoA) and investigate the correlation between neurotransmitter levels and clinical indicators. A total of 28 patients with MWoA and 28 sex-, age-, and education level–matched healthy controls (HCs) underwent single-voxel proton magnetic resonance spectroscopy scanning at 3.0 Tesla. MEscher-Garwood Point RESolved Spectroscopy (MEGA-PRESS) sequence was performed to acquire the spectral data of GABA and Glx in the ACC and mPFC. The clinical indicators and anxiety-depression states of all participants were assessed. The acquired GABA signal contained the overlapping signals of macromolecules and homocarnosine, hence expressed as GABA+. The creatine (Cr) signal was applied as an endogenous reference. We observed that GABA+/Cr levels were significantly lower in ACC and mPFC of patients with MWoA than of HCs, with no significant difference in Glx levels. Negative correlations between GABA+/Cr levels and attack frequency were found in the ACC and mPFC regions of patients. These results suggested that there might be a close relationship between ACC and mPFC GABAergic neurons abnormalities and the pathophysiological mechanisms of MWoA. It might be beneficial to targeted treatment for patients with MWoA.

Cortical GABA levels are reduced in young adult binge drinkers: Association with recent alcohol consumption and sex

Binge drinking refers to a pattern of alcohol intake that raises blood alcohol concentration to or above legal intoxication levels. It is common among young adults and is associated with health risks that scale up with alcohol intake. Acute intoxication depresses neural activity via complex signaling mechanisms by enhancing inhibition mediated by gamma-amino butyric acid (GABA), and by decreasing excitatory glutamatergic effects. Evidence primarily rooted in animal research indicates that the brain compensates for the acute depressant effects under the conditions of habitual heavy use. These neuroadaptive changes are reflected in neural hyperexcitability via downregulated inhibitory signaling, which becomes apparent as withdrawal symptoms. However, human evidence on the compensatory reduction in GABA signaling is scant. The neurochemical aspect of this mechanistic model was evaluated in the present study with proton magnetic resonance spectroscopy (1H-MRS) which is sensitive to GABA plus macromolecule signal (GABA + ). Furthermore, we examined sex differences in GABA + levels as a function of a recent history of binge drinking, given interactions between endogenous neurosteroids, GABA signaling, and alcohol.The study recruited young adult women and men (22.2 ± 2.8 years of age) who were classified as binge drinkers (BDs, N = 52) if they reported ≥ 5 binge episodes in the previous six months. Light drinkers (LDs, N = 49) reported drinking regularly, but not exceeding ≤ 2 binge episodes in the past six months. GABA-edited 1H-MR spectra were acquired from the occipital cortex at 3 T with the MEGA-PRESS sequence. GABA + signal was analyzed relative to water and total creatine (Cr) levels as a function of binge drinking history and sex. Controlling for within-voxel tissue composition, both GABA + indices showed decreased GABA + levels in BDs relative to LDs. The reduced GABA + concentration was associated with occasional high-intensity drinking in the BD group.This evidence is consistent with compensatory GABA downregulation that accompanies alcohol misuse, tipping the excitation/inhibition balance towards hyperexcitability. Analysis of the time course of GABA + neuroplasticity indicated that GABA + was lowest when measured one day after the last drinking occasion in BDs. While the BD vs LD differences were primarily driven by LD women, there was no interaction between Sex and a history of binge drinking. GABA + was higher in LD women compared to LD men.Aligned with the allostasis model, the mechanistic compensatory GABA downregulation observed in young emerging adults engaging in occasional binge drinking complements direct neural measures of hyperexcitability in BDs. Notably, these results suggest that neuroadaptation to alcohol is detectable at the levels of consumption that are within a normative range, and may contribute to adverse health outcomes.

Comprehensive bioinformatic analysis of key genes and signaling pathways in glioma

The identification of specific survival-related differentially expressed genes (DEGs) is a method for uncovering therapeutic approaches for various cancers, including glioma. However, the key target genes associated with the occurrence and development of gliomas remain unknown. In this study, we performed bioinformatics analysis on 17 GSE datasets and identified DEGs correlated with glioma. A total of 74 mutual-DEGs with downregulated expression in gliomas compared with that in normal brain tissues were found in 17 datasets. These DEGs were related to GABAergic synaptic transmission, chloride transmembrane transport, glutamate secretion, and gamma-aminobutyric acid signaling pathway. Gamma-aminobutyric acid type A receptor subunit gamma 2 (GABRG2) was identified as a hub gene in the protein-protein interaction network. GABRG2 exhibited lower expression in IDH wild-type astrocytoma than that in IDH mutant astrocytoma and indicated poor prognosis in glioma patients. GABRG2 may contribute to the progression of glioma by affecting GABA receptor-related pathways and is a potential biomarker for the diagnosis and treatment of glioma.

GABAergic Modulation in Movement Related Oscillatory Activity: A Review of the Effect Pharmacologically and with Aging

Gamma-aminobutyric acid (GABA) is a ubiquitous inhibitory neurotransmitter critical to the control of movement both cortically and subcortically. Modulation of GABA can alter the characteristic rest as well as movement-related oscillatory activity in the alpha (8–12 Hz), beta (13–30 Hz, and gamma (60–90 Hz) frequencies, but the specific mechanisms by which GABAergic modulation can modify these well-described changes remains unclear. Through pharmacologic GABAergic modulation and evaluation across the age spectrum, the contributions of GABA to these characteristic oscillatory activities are beginning to be understood. Here, we review how baseline GABA signaling plays a key role in motor networks and in cortical oscillations detected by scalp electroencephalography and magnetoencephalography. We also discuss the data showing specific alterations to baseline movement related oscillatory changes from pharmacologic intervention on GABAergic tone as well as with healthy aging. These data provide greater insight into the physiology of movement and may help improve future development of novel therapeutics for patients who suffer from movement disorders.

The effect of age and sex on the expression of GABA signaling components in the human hippocampus and entorhinal cortex

Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the nervous system. The GABA signaling system in the brain is comprised of GABA synthesizing enzymes, transporters, GABAA and GABAB receptors (GABAAR and GABABR). Alterations in the expression of these signaling components have been observed in several brain regions throughout aging and between sexes in various animal models. The hippocampus is the memory centre of the brain and is impaired in several age-related disorders. It is composed of two main regions: the Cornu Ammonis (CA1-4) and the Dentate Gyrus (DG), which are interconnected with the Entorhinal Cortex (ECx). The age- and sex-specific changes of GABA signaling components in these regions of the human brain have not been examined. This study is the first to determine the effect of age and sex on the expression of GABA signaling components-GABAAR α1,2,3,5, β1-3, γ2, GABABR R1 and R2 subunits and the GABA synthesizing enzymes GAD 65/67-in the ECx, and the CA1 and DG regions of the human hippocampus using Western blotting. No significant differences were found in GABAAR α1,2,3,5, β1-3, γ2, GABABR R1 and R2 subunit and GAD65/76 expression levels in the ECx, CA1 and DG regions between the younger and older age groups for both sexes. However, we observed a significant negative correlation between age and GABAAR α1subunit level in the CA1 region for females; significant negative correlation between age and GABAAR β1, β3 and γ2 subunit expression in the DG region for males. In females a significant positive correlation was found between age and GABAAR γ2 subunit expression in the ECx and GABABR R2 subunit expression in the CA1 region. The results indicate that age and sex do not affect the expression of GAD 65/67. In conclusion, our results show age- and sex-related GABAA/BR subunit alterations in the ECx and hippocampus that might significantly influence GABAergic neurotransmission and underlie disease susceptibility and progression.

GAD67-mediated GABA Synthesis and Signaling Impinges on Directing Basket Cell Axonal Projections Toward Purkinje Cells in the Cerebellum.

Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the central nervous system, synthesized by two isoforms of glutamate decarboxylase (GAD): GAD65 and GAD67. GABA may act as a trophic factor during brain development, but its contribution to the development and maturation of cerebellar neural circuits is not known. To understand the roles of GABA in cerebellar organization and associated functions in motor coordination and balance, we examined GAD65 conventional knock out (KO) mice and mice in which GAD67 was eliminated in parvalbumin-expressing neurons (PV-Cre; GAD67flox/flox mice). We found aberrant subcellular localization of the Shaker-type K channel Kv1.1 in basket cell collaterals of PV-Cre; GAD67 flox/flox mice and abnormal projections from basket cells to Purkinje cells in both mouse strains. We also found that altered synaptic properties of basket cell terminals to Purkinje cells in PV-Cre; GAD67flox/flox mice. Furthermore, PV-Cre; GAD67 flox/flox mice exhibited abnormal motor coordination in the rotarod test. These results indicate that GABA signaling in the cerebellum is critical for establishing appropriate connections between basket cells and Purkinje cells and is associated with motor coordination in mice.

Regional specificity and clinical correlates of cortical GABA alterations in posttraumatic stress disorder.

Gamma-aminobutyric acid (GABA) metabolism is implicated in posttraumatic stress disorder (PTSD) and may be altered in prefrontal-limbic brain regions involved in arousal regulation. This study used proton magnetic resonance spectroscopy (MRS) to test the hypothesis that PTSD and trauma-exposed non-PTSD comparison (TENC) adults have significantly different GABA than healthy comparison (HC) subjects in two brain areas implicated in arousal (medial prefrontal cortex, insula) but not in a control brain area (posterior temporal cortex). We also examined whether GABA alterations correlated with hyperarousal and dissociation symptoms. One hundred and fourteen participants (39 PTSD, 34 TENC, 41 HC) underwent 3T MRS of the medial prefrontal, right insular, and right posterior temporal cortices, and the GABA plus macromolecule signal (GABA+) was normalized to creatine (Cr). The Clinician Administered PTSD Scale measured hyperarousal symptoms, including sleep disruption. The Dissociative Experiences Scale assessed dissociation symptoms. PTSD and TENC participants had significantly lower mPFC GABA+/Cr than HC participants, and this deficit was significantly correlated with greater dissociation. Compared with HC, PTSD patients but not TENC had significantly lower insula GABA+/Cr. Total hyperarousal symptoms and sleep disruption were not significantly associated with GABA+/Cr alterations in either region. Our findings point to lower GABA in cortical areas implicated in arousal regulation in PTSD and suggest that GABA alterations are associated with symptoms of trauma-related psychopathology but not always a biomarker of diagnosis. These findings also add to evidence that dissociation has distinct neural correlates within PTSD, including high excitability of medial prefrontal cortex.