Interplay between microbial-derived GABA and host GABA receptor signaling collectively influence the tumorigenic function of GABA in colon cancer.

Although classically recognized as a neurotransmitter, gamma aminobutyric acid (GABA) has also been identified in colonic tumors. Moreover, the gut microbiome represents another potential source of GABA. Both GABAA and GABAB receptors have been implicated in contributing to the effects of GABA in colorectal cancer, with both pro- and anti-tumorigenic functions identified. However, their subunit composition is often overlooked. Studies to date have not addressed whether the GABA-producing potential of the microbiome changes over the course of colon tumor development or whether receptor subunit expression patterns are altered in colon cancer. Therefore, we investigated the clusters of orthologous group frequencies of glutamate decarboxylase (GAD) in feces from two murine models of colon cancer and found that the frequency of microbial GAD was significantly decreased early in the tumorigenic process. We also determined that microbial-derived GABA inhibited proliferation of colon cancer cells in vitro and that this effect of GABA on SW480 cells involved both GABAA and GABAB receptors. GABA also inhibited prostaglandin E2 (PGE2)-induced proliferation and interleukin-6 (IL-6) expression in these cells. Gene expression correlations were assessed using the "Cancer Exploration" suite of the TIMER2.0 web tool and identified that GABA receptor subunits were differentially expressed in human colon cancer. Moreover, GABAA receptor subunits were predominantly positively associated with PGE2 synthase, cyclooxygenase-2 and IL-6. Collectively, these data demonstrate decreased potential of the microbiome to produce GABA during tumorigenesis, a novel anti-tumorigenic pathway for GABA, and that GABA receptor subunit expression adds a further layer of complexity to GABAergic signaling in colon cancer.

Role of ß3 subunit of the GABA type A receptor in triple negative breast cancer proliferation, migration, and cell cycle progression.

Triple negative breast cancer (TNBC) is known for its heterogeneous nature and aggressive onset. The unresponsiveness to hormone therapies and immunotherapy and the toxicity of chemotherapeutics account for the limited treatment options for TNBC. Ion channels have emerged as possible therapeutic candidates for cancer therapy, but little is known about how ligand gated ion channels, specifically, GABA type A ligand-gated ion channel receptors (GABAAR), affect cancer pathogenesis. Our results show that the GABAA ß3 subunit is expressed at higher levels in TNBC cell lines than non-tumorigenic cells, therefore contributing to the idea that limiting the GABAAR via knockdown of the GABAA ß3 subunit is a potential strategy for decreasing the proliferation and migration of TNBC cells. We employed pharmacological and genetic approaches to investigate the role of the GABAA ß3 subunit in TNBC proliferation, migration, and cell cycle progression. The results suggest that pharmacological antagonism or genetic knockdown of GABAA ß3 subunit decreases TNBC proliferation and migration. In addition, GABAA ß3 subunit knockdown causes cell cycle arrest in TNBC cell lines via decreased cyclin D1 and increased p21 expression. Our findings suggest that membrane bound GABAA receptors containing the ß3 subunit can be further developed as a potential novel target for the treatment of TNBC.

Positive association between dehydroepiandrosterone (DHEA) and gene expression of the gamma-aminobutyric acid (GABA-A) receptor δ subunit.

Gamma-aminobutyric acid A (GABA-A) receptors in the cells of the immune system enhance anti-inflammatory responses by regulating cytokine secretion, cytotoxic responses, and cell activation. In the CNS, the formation of GABA-A subunits into a pentameric structure has been extensively studied; however, no such study has been conducted in the immune system. The objective of the present study was to examine associations between the levels of steroid hormones and GABA-A receptor δ subunit expression in the immune system. We focused on this subunit because GABA-A receptors that contain it become significantly more sensitive to steroid hormones. We collected 80 blood samples from reproductive age women for the purpose of analyzing dehydroepiandrosterone (DHEA), 17ß-estradiol, progesterone, and allopregnanolone using liquid chromatography-mass spectrometry (LC-MS). Furthermore, we extracted peripheral blood mononuclear cells (PBMCs) for determining mRNA expression levels of GABA-A receptor genes encoding the δ and ε subunits. We constructed linear mixed effect models for each GABA-A receptor subunit with all 4 steroid hormones, age, and age of menarche as predictors. Whereas DHEA was significantly associated with δ subunit expression (t-value = 2.981; p = 0.003), in line with our hypothesis, none of the steroid hormones were significantly associated with the expression of the ε subunit. Results of this study indicate that significant interactions between hormones from the steroid hormone biosynthesis pathway and GABAergic machinery from the immune cells may be utilized to expand models examining the molecular basis of inflammatory conditions.

A potassium-chloride co-transporter with altered genome architecture functions as a suppressor in glioma.

Gliomas, the most lethal tumours in brain, have a poor prognosis despite accepting standard treatment. Limited benefits from current therapies can be attributed to genetic, epigenetic and microenvironmental cues that affect cell programming and drive tumour heterogeneity. Through the analysis of Hi-C data, we identified a potassium-chloride co-transporter SLC12A5 associated with disrupted topologically associating domain which was downregulated in tumour tissues. Multiple independent glioma cohorts were included to analyse the characterization of SLC12A5 and found it was significantly associated with pathological features, prognostic value, genomic alterations, transcriptional landscape and drug response. We constructed two SLC12A5 overexpression cell lines to verify the function of SLC12A5 that suppressed tumour cell proliferation and migration in vitro. In addition, SLC12A5 was also positively associated with GABAA receptor activity and negatively associated with pro-tumour immune signatures and immunotherapy response. Collectively, our study provides a comprehensive characterization of SLC12A5 in glioma and supports SLC12A5 as a potential suppressor of disease progression.

Increased GABA signaling in liver macrophage promotes HBV replication in HBV-carrier mice.

Gamma-aminobutyric acid (GABA) signals in various non-neuronal cells including hepatocytes and some immune cells. Studies, including ours, show that type A GABA receptors (GABAARs)-mediated signaling occurs in macrophages regulating tissue-specific functions. Our recent study reveals that activation of GABAARs in liver macrophages promotes their M2-like polarization and increases HBV replication in mice. This short article briefly summarizes the GABA signaling system in macrophages and discusses potential mechanisms by which GABA signaling promotes HBV replication.

Gender-related variation expressions of neuroplastin TRAF6, GluA1, GABA(A) receptor, and PMCA in cortex, hippocampus, and brainstem in an experimental epilepsy model.

Epileptic seizures are seen as a result of changing excitability balance depending on the deterioration in synaptic plasticity in the brain. Neuroplastin, and its related molecules which are known to play a role in synaptic plasticity, neurotransmitter activities that provide balance of excitability and, different neurological diseases, have not been studied before in epilepsy. In this study, a total of 34 Sprague-Dawley male and female rats, 2 months old, weighing 250-300 g were used. The epilepsy model in rats was made via pentylenetetrazole (PTZ). After the completion of the experimental procedure, the brain tissue of the rats were taken and the histopathological changes in the hippocampus and cortex parts and the brain stem were investigated, as well as the immunoreactivity of the proteins related to the immunohistochemical methods. As a result of the histopathological evaluation, it was determined that neuron degeneration and the number of dilated blood vessels in the hippocampus, frontal cortex, and brain stem were higher in the PTZ status epilepticus (SE) groups than in the control groups. It was observed that neuroplastin and related proteins TNF receptor-associated factor 6 (TRAF6), Gamma amino butyric acid type A receptors [(GABA(A)], and plasma membrane Ca2+ ATPase (PMCA) protein immunoreactivity levels increased especially in the male hippocampus, and only AMPA receptor subunit type 1 (GluA1) immunoreactivity decreased, unlike other proteins. We believe this may be caused by a problem in the mechanisms regulating the interaction of neuroplastin and GluA1 and may cause problems in synaptic plasticity in the experimental epilepsy model. It may be useful to elucidate this mechanism and target GluA1 when determining treatment strategies.

Comparison of the negative effect of remimazolam and propofol on cardiac contractility: Analysis of a randomised parallel-group trial and a preclinical ex vivo study.

Remimazolam is a newly developed ultra-short-acting benzodiazepine that exerts sedative effects. This study aimed to clarify the effects of remimazolam on cardiac contractility. In a randomised-parallel group trial, haemodynamic parameters were compared between propofol (n = 11) and remimazolam (n = 12) groups during the induction of general anaesthesia in patients undergoing non-cardiac surgery. In a preclinical study, the direct effects of remimazolam on cardiac contractility were also evaluated using isolated rat hearts. RNA sequence data obtained from rat and human hearts were analysed to assess the expression patterns of the cardiac γ-aminobutyric acid type A (GABAA ) receptor subunits. In a clinical study, the proportional change of the maximum rate of arterial pressure rise was milder during the study period in the remimazolam group (propofol: -52.6 [10.2] (mean [standard deviation])% vs. remimazolam: -39.7% [10.5%], p = 0.007). In a preclinical study, remimazolam did not exert a negative effect on left ventricle developed pressure, whereas propofol did exert a negative effect after bolus administration of a high dose (propofol: -26.9% [3.5%] vs. remimazolam: -1.1 [6.9%], p < 0.001). Analysis of the RNA sequence revealed a lack of γ subunits, which are part of the major benzodiazepine binding site of the GABAA receptor, in rat and human hearts. These results indicate that remimazolam does not have a direct negative effect on cardiac contractility, which might contribute to its milder effect on cardiac contractility during the induction of general anaesthesia. The expression patterns of cardiac GABAA receptor subunits might be associated with the unique pharmacokinetics of benzodiazepines in the heart.

GABRP Promotes the Metastasis of Pancreatic Cancer by Activation of the MEK/ERK Signaling Pathway.

Pancreatic cancer remains the common cancer with the worst prognosis because of its late diagnosis and extensive metastasis. This study aimed to investigate the effects of GABRP on pancreatic cancer metastasis and the molecular mechanism. The expression of GABRP was measured using the quantitative real-time PCR and western blot. The biological behaviors of cancer cells were assessed using the cell counting kit-8, Transwell assay, and western blot. The regulation of GABRP on the MEK/ERK pathway was detected by western blot. The results indicated that GABRP was overexpressed in pancreatic cancer tissues and cells. Knockdown of GABRP suppressed cell viability, invasion, migration, and epithelial-mesenchymal transition (EMT), whereas GABRP overexpression facilitated these biological behaviors. Inactivation of the MEK/ERK pathway reversed the effects on cellular processes induced by GABRP. Moreover, silencing of GABRP inhibited tumor growth. In conclusion, GABRP promoted the progression of pancreatic cancer by facilitating cell metastasis and tumor growth via activating the MEK/ERK pathway. The findings suggest that GABRP has the potential to be a therapeutic target for the metastatic pancreatic cancer.

Muscimol inhibits plasma membrane rupture and ninjurin-1 oligomerization during pyroptosis.

Pyroptosis is a cell death process that causes inflammation and contributes to numerous diseases. Pyroptosis is mediated by caspase-1 family proteases that cleave the pore-forming protein gasdermin D, causing plasma membrane rupture and release of pathogenic cellular contents. We previously identified muscimol as a small molecule that prevents plasma membrane rupture during pyroptosis via an unidentified mechanism. Here, we show that muscimol has reversible activity to prevent cellular lysis without affecting earlier pyroptotic events. Although muscimol is a well-characterized agonist for neuronal GABAA receptors, muscimol protection is not altered by GABAA receptor antagonists or recapitulated by other GABAA agonists, suggesting that muscimol acts via a novel mechanism. We find that muscimol blocks oligomerization of ninjurin-1, which is required for plasma membrane rupture downstream of gasdermin D pore formation. Our structure-activity relationship studies reveal distinct molecular determinants defining inhibition of pyroptotic lysis compared to GABAA binding. In addition, we demonstrate that muscimol reduces lethality during LPS-induced septic shock. Together, these findings demonstrate that ninjurin-1-mediated plasma membrane rupture can be pharmacologically modulated and pave the way toward identification of therapeutic strategies for pathologic conditions associated with pyroptosis.

Cyclin D1-Cdk4 regulates neuronal activity through phosphorylation of GABAA receptors.

Nuclear Cyclin D1 (Ccnd1) is a main regulator of cell cycle progression and cell proliferation. Interestingly, Ccnd1 moves to the cytoplasm at the onset of differentiation in neuronal precursors. However, cytoplasmic functions and targets of Ccnd1 in post-mitotic neurons are unknown. Here we identify the α4 subunit of gamma-aminobutyric acid (GABA) type A receptors (GABAARs) as an interactor and target of Ccnd1-Cdk4. Ccnd1 binds to an intracellular loop in α4 and, together with Cdk4, phosphorylates the α4 subunit at threonine 423 and serine 431. These modifications upregulate α4 surface levels, increasing the response of α4-containing GABAARs, measured in whole-cell patch-clamp recordings. In agreement with this role of Ccnd1-Cdk4 in neuronal signalling, inhibition of Cdk4 or expression of the non-phosphorylatable α4 decreases synaptic and extra-synaptic currents in the hippocampus of newborn rats. Moreover, according to α4 functions in synaptic pruning, CCND1 knockout mice display an altered pattern of dendritic spines that is rescued by the phosphomimetic α4. Overall, our findings molecularly link Ccnd1-Cdk4 to GABAARs activity in the central nervous system and highlight a novel role for this G1 cyclin in neuronal signalling.

Comprehensive Analysis of the Expression, Prognostic Value, and Immune Infiltration Activities of GABRD in Colon Adenocarcinoma.

Colon adenocarcinoma (COAD) is one of the tumors with the highest mortality rates. It is of the utmost significance to make an accurate prognostic assessment and to tailor one's treatment to the specific needs of the patient. Multiple lines of evidence point to the possibility that genetic variables and clinicopathological traits are connected to the onset and development of cancer. In the past, a number of studies have revealed that gamma-aminobutyric acid type A receptor subunit delta (GABRD) plays a role in the advancement of a number of different cancers. However, its function in COAD was rarely reported. In this study, we analyzed TCGA datasets and identified 29 survival-related differentially expressed genes (DEGs) in COAD patients. In particular, GABRD expression was noticeably elevated in COAD specimens. There was a correlation between high GABRD expression and an advanced clinical stage. According to the results of the survival tests, patients whose GABRD expression was high had a lower overall survival time and progression-free survival time than those whose GABRD expression was low. GABRD expression was found to be an independent predictive predictor for overall survival, as determined by multivariate COX regression analysis. Additionally, the predictive nomogram model can accurately predict the fate of individuals with COAD. In addition, we observed that GABRD expressions were positively associated with the expression of T cells regulatory (Tregs), macrophages M0, while negatively associated with the expression of T cells CD8, T cells follicular helper, macrophages M1, dendritic cells activated, eosinophils, and T cells CD4 memory activated. The IC50 of BI-2536, bleomycin, embelin, FR-180204, GW843682X, LY317615, NSC-207895, rTRAIL, and VX-11e was higher in the GABRD high-expression group. In conclusion, we have shown evidence that GABRD is a novel biomarker that is connected with immune cell infiltration in COAD and may be utilized to predict the prognosis of COAD patients.

Novel variants in GABAA receptor subunits: A possible association with benzodiazepine resistance in patients with drug-resistant epilepsy.

Benzodiazepines (BDZ) such as diazepam and lorazepam are popular as first-line treatment for acute seizures due to their rapid action and high efficacy. However, long-term usage of BDZ leads to benzodiazepine resistance, a phenomenon whose underlying mechanisms are still being investigated. One of the hypothesised mechanisms contributing to BDZ resistance is the presence of mutations in benzodiazepine-sensitive receptors. While a few genetic variants have been reported previously, knowledge of relevant pathogenic variants is still scarce. We used Sanger Sequencing to detect variants in the ligand-binding domain of BDZ-sensitive GABAA receptor subunits α1-3 and 5 expressed in resected brain tissues of drug-resistant epilepsy (DRE) patients with a history of BDZ resistance and found two previously unreported predicted pathogenic frameshifting variants - NM_000807.4(GABRA2):c.367_368insG and NM_000810.4(GABRA5):c.410del - significantly enriched in these patients. The findings were further explored in resected DRE brain tissues through cellular electrophysiological experiments.

Genetic interaction between GABRA1 and ERBB4 variants in the pathogenesis of genetic generalized epilepsy.

Epilepsy is a complex neurological disease that can be caused by both genetic and environmental factors. Many studies have been conducted to investigate the genetic risk variants and molecular mechanisms of epilepsy. Disruption of excitation-inhibition balance (E/I balance) is one of the widely accepted disease mechanisms of epilepsy. The maintenance of E/I balance is an intricate process that is governed by multiple proteins. Using whole exome sequencing (WES), we identified a novel GABRA1 c.448G>A (p.E150K) variant and ERBB4 c.1972A>T (p.I658F, rs190654033) variant in a Malaysian Chinese family with genetic generalized epilepsy (GGE). The GGE may be triggered by dysregulation of E/I balance mechanism. Segregation of the variants in the family was verified by Sanger sequencing. All family members with GGE inherited both variants. However, family members who carried only one of the variants did not show any symptoms of GGE. Both the GABRA1 and ERBB4 variants were predicted damaging by MutationTaster and CADD, and protein structure analysis showed that the variants had resulted in the formation of additional hydrogen bonds in the mutant proteins. GABRA1 variant could reduce the efficiency of GABAA receptors, and constitutively active ERBB4 receptors caused by the ERBB4 variant promote internalization of GABAA receptors. The interaction between the two variants may cause a greater disruption in E/I balance, which is more likely to induce a seizure. Nevertheless, this disease model was derived from a single small family, further studies are still needed to confirm the verifiability of the purported disease model.

Prospective DNA Methylation Analysis of the CpG GABRA2 Receptor Subunit in Alcohol Dependence during Detoxification.

Background and Objectives: Variants of GABRA2 have been repeatedly associated with alcohol dependence risk. However, no study investigated potential epigenetic alterations in the GABRA2 gene in alcohol-dependent (AD) subjects during alcohol withdrawal. We investigated DNA methylation pattern in the regulatory region of GABRA2 gene in peripheral leukocytes of AD patients and controls. Further, GABRA2 methylation patterns were analysed in neuroblastoma cells under ethanol exposure and withdrawal. Materials and Methods: In the present study, blood samples were obtained from 41 AD subjects on the day of inpatient admission, after the first and second week of inpatient treatment. The comparison group included 47 healthy controls. GABRA2 methylation of 4 CpG sites in the CpG island was compared to neuroblastoma cells which were exposed to 100 mM of ethanol for 2, 5 and 9 days, followed by a withdrawal interval of 4 days. Results: no significant differences in GABRA2 methylation patterns were found in AD subjects over time and vs. controls, after controlling for age. Further, no influence of withdrawal severity, alcohol consumption before admission and other alcohol dependence characteristics were found. Conclusions: The results indicate that GABRA2 methylation in AD individuals and in a cell model is unaffected by alcohol exposition and withdrawal. Influences of GABRA2 on characteristics of alcohol dependence may be exerted by mechanisms other than epigenetic alterations related to alcohol intoxication or withdrawal.

Activation of the Rat α1ß2ε GABAA Receptor by Orthosteric and Allosteric Agonists.

GABAA receptors are a major contributor to fast inhibitory neurotransmission in the brain. The receptors are activated upon binding the transmitter GABA or allosteric agonists including a number of GABAergic anesthetics and neurosteroids. Functional receptors can be formed by various combinations of the nineteen GABAA subunits cloned to date. GABAA receptors containing the ε subunit exhibit a significant degree of constitutive activity and have been suggested to be unresponsive to allosteric agents. In this study, we have characterized the functional properties of the rat α1ß2ε GABAA receptor. We confirm that the α1ß2ε receptor exhibits a higher level of constitutive activity than typical of GABAA receptors and show that it is inefficaciously activated by the transmitter and the allosteric agonists propofol, pentobarbital, and allopregnanolone. Manipulations intended to alter ε subunit expression and receptor stoichiometry were largely without effect on receptor properties including sensitivity to GABA and allosteric agonists. Surprisingly, amino acid substitutions at the conserved 9' and 6' positions in the second transmembrane (TM2) domain in the ε subunit did not elicit the expected functional effects of increased constitutive activity and resistance to the channel blocker picrotoxin, respectively. We tested the accessibility of TM2 residues mutated to cysteine using the cysteine-modifying reagent 4-(hydroxymercuri)benzoic acid and found a unique pattern of water-accessible residues in the ε subunit.

Effects of α5 GABAA receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer's disease.

AIMS: GABAergic modulation involved in cognitive processing appears to be substantially changed in Alzheimer's disease (AD). In a widely used 5xFAD model of AD, we aimed to assess if negative and positive allosteric modulators of α5 GABAA receptors (NAM and PAM, respectively) would affect social interaction, social, object and spatial memory, and neuroinflammation. METHODS: After 10-day treatment with PAM, NAM, or solvent, 6-month-old transgenic and non-transgenic 5xFAD mice underwent testing in a behavioral battery. Gene expressions of IL-1ß, IL-6, TNF-α, GFAP, and IBA-1 were determined in hippocampus and prefrontal cortex by qPCR. RESULTS: PAM treatment impaired spatial learning in transgenic females compared to solvent-treated transgenic females, and social recognition in transgenic and non-transgenic males. NAM treatment declined social interaction in transgenic and non-transgenic males, while had beneficial effect on cognitive flexibility in non-transgenic males compared to solvent-treated non-transgenic males. Transgenic animals have not fully displayed cognitive symptoms, but neuroinflammation was confirmed. NAM reduced proinflammatory gene expressions in transgenic females and astrogliosis in transgenic males compared to pathological controls. CONCLUSION: PAM and NAM failed to exert favorable behavioral effects in transgenic animals. Suppression of neuroinflammation obtained with NAM calls for more studies with GABAergic ligands in amyloid beta- and/or tau-dependent models with prominent neuroinflammation.

Molecular Mechanisms of Epilepsy: The Role of the Chloride Transporter KCC2.

Epilepsy is a neurological disease characterized by abnormal or synchronous brain activity causing seizures, which may produce convulsions, minor physical signs, or a combination of symptoms. These disorders affect approximately 65 million people worldwide, from all ages and genders. Seizures apart, epileptic patients present a high risk to develop neuropsychological comorbidities such as cognitive deficits, emotional disturbance, and psychiatric disorders, which severely impair quality of life. Currently, the treatment for epilepsy includes the administration of drugs or surgery, but about 30% of the patients treated with antiepileptic drugs develop time-dependent pharmacoresistence. Therefore, further investigation about epilepsy and its causes is needed to find new pharmacological targets and innovative therapeutic strategies. Pharmacoresistance is associated to changes in neuronal plasticity and alterations of GABAA receptor-mediated neurotransmission. The downregulation of GABA inhibitory activity may arise from a positive shift in GABAA receptor reversal potential, due to an alteration in chloride homeostasis. In this paper, we review the contribution of K+-Cl--cotransporter (KCC2) to the alterations in the Cl- gradient observed in epileptic condition, and how these alterations are coupled to the increase in the excitability.

Long non-coding RNA Gm37494 alleviates osteoarthritis chondrocyte injury via the microRNA-181a-5p/GABRA1 axis.

OBJECTIVE: This study was conducted to investigate the effect of long non-coding RNA (lncRNA) Gm37494 on osteoarthritis (OA) and its related molecular mechanism. METHODS: The cartilage tissues were obtained from OA patients, and an OA mouse model was induced by the destabilization of the medial meniscus, followed by measurement of Gm37494, microRNA (miR)-181a-5p, GABRA1 mRNA, and the encoded GABAARα1 protein expression. Thereafter, a cellular model was induced by interleukin-1ß (IL-1ß) treatment in chondrocytes, followed by ectopic and silencing experiments. Chondrocyte proliferation was detected by CCK-8 and EdU assays, chondrocyte apoptosis by flow cytometry and western blot, and the levels of inflammatory factors by ELISA. The binding of Gm37494 to miR-181a-5p was evaluated by dual-luciferase reporter gene and RIP assays, and that of GABRA1 to miR-181a-5p by dual-luciferase reporter gene and RNA pull-down assays. RESULTS: OA patients and mice had decreased GABRA1 mRNA and GABAARα1 protein levels and elevated miR-181a-5p expression in cartilage tissues. Additionally, Gm37494 was poorly expressed in OA mice. Mechanistically, Gm37494 directly bound to and inversely modulated miR-181a-5p that negatively targeted GABRA1. In IL-1ß-induced chondrocytes, Gm37494 overexpression enhanced cell proliferation and suppressed cell apoptosis and inflammation, whereas further miR-181a-5p up-regulation or GABRA1 silencing abolished these trends. CONCLUSIONS: Conclusively, Gm37494 elevated GABRA1 expression by binding to miR-181a-5p, thus ameliorating OA-induced chondrocyte damage.

Effects of Risperidone and Prenatal Poly I:C Exposure on GABAA Receptors and AKT-GSK3ß Pathway in the Ventral Tegmental Area of Female Juvenile Rats.

The ventral tegmental area (VTA) in the ventral midbrain is the origin of the dopaminergic neurotransmission pathways. Although GABAA receptors and AKT-GSK3ß signaling are involved in the pathophysiology of mental disorders and are modulated by antipsychotics, an unmet task is to reveal the pathological changes in these biomarkers and antipsychotic modulations in the VTA. Using a juvenile polyriboinosinic-polyribocytidylic acid (Poly I:C) psychiatric rat model, this study investigated the effects of adolescent risperidone treatment on GABAA receptors and AKT/GSK3ß in the VTA. Pregnant female Sprague-Dawley rats were administered Poly I:C (5mg/kg; i.p) or saline at gestational day 15. Juvenile female offspring received risperidone (0.9 mg/kg, twice per day) or a vehicle from postnatal day 35 for 25 days. Poly I:C offspring had significantly decreased mRNA expression of GABAA receptor ß3 subunits and glutamic acid decarboxylase (GAD2) in the VTA, while risperidone partially reversed the decreased GAD2 expression. Prenatal Poly I:C exposure led to increased expression of AKT2 and GSK3ß. Risperidone decreased GABAA receptor ß2/3, but increased AKT2 mRNA expression in the VTA of healthy rats. This study suggests that Poly I:C-elicited maternal immune activation and risperidone differentially modulate GABAergic neurotransmission and AKT-GSK3ß signaling in the VTA of adolescent rats.