Hippocampal Gamma-aminobutyric Acid Research Articles

Essential oil of Pterocarpus santalinus L. alleviates behavioral impairments in social defeat stress-exposed mice by regulating neurotransmission and neuroinflammation

BackgroundPterocarpus santalinus L. essential oil (PSEO) is traditionally employed for treating fever and mental aberrations. We aim to explore the antidepressant potential of intranasal PSEO in social defeat stress (SDS)-expose mice and identify its mechanisms and components. MethodsPSEO components were analyzed using gas chromatography-mass spectrometry (GC-MS). C57BL/6 mice underwent a 10-day SDS with intranasal PSEO (10, 20 mg/kg) for 21 days. Efficacy was evaluated through changes in behaviors and serum corticosterone (CORT), hippocampal neurotransmitter, and inflammatory cytokine levels. In vitro effects were examined using primary hippocampal neurons, PC12 and BV2 cells. ResultsGC-MS identified 22 volatile compounds in PSEO, and (+)-ledene (16.7%), cedrol (13.5%), and isoaromadendrene epoxide (7.0%) as major components. PSEO (20 mg/kg) significantly reversed SDS-induced social withdrawal, increased open-area explorations in the open field test (OFT) and elevated plus maze (EPM) test, and reduced immobility time in the tail suspension test (TST) and forced swimming test (FST). PSEO downregulated serum CORT and hippocampal interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α levels, while increasing hippocampal gamma-aminobutyric acid (GABA), norepinephrine (NE), and serotonin (5-HT) levels. PSEO (0.1, 1, 10 µg/mL) reduced neurotoxicity and neuroinflammation in PC12 and BV2 cells, respectively. PSEO (10 µg/mL) enhanced glutamic acid decarboxylase 6 (GAD6)- and GABA B receptor 1 (GABABR1)-positive puncta in the hippocampal neurons and FM1-43 fluorescence intensity. ConclusionIntranasal PSEO exhibited antidepressant-like effects on SDS-exposed mice, potentially through modulating stress hormone, neurotransmission, and neuroinflammation. Further investigation into the pharmacokinetics, bioavailability, and mechanisms of (+)-ledene, cedrol, and isoaromadendrene epoxide is needed.

Vitamin B6 Deficiency Induces Autism-Like Behaviors in Rats by Regulating mTOR-Mediated Autophagy in the Hippocampus.

Vitamin B6 (VB6) exhibits therapeutic effects towards autism spectrum disorder (ASD), but its specific mechanism is poorly understood. Rat dams were treated with VB6 standard, VB6 deficiency, or VB6 supplementary diet, and the same treatment was provided to their offspring, with their body weights monitored. Three-chambered social test and open field test were employed to evaluate the effect of VB6 on autism-like behaviors. Gamma-aminobutyric acid (GABA) generation and synaptic inhibition of neurons in the hippocampus of rat were detected via immunofluorescence staining, followed by the measurement of GABA concentration through high-performance liquid chromatography (HPLC). The role of VB6 in the autophagy and apoptosis of cells was determined via Western blot and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). In order to conduct rescue experiments, the inhibition of mammalian target of rapamycin (mTOR) or the activation of GABA was achieved by drug administration to the offspring rats with VB6 deficiency. As a result, no evident difference in weight was observed in the offspring with varied VB6 treatments. VB6 deficiency impaired social interaction; aggravated self-grooming and bowel frequency; decreased GABA concentration, VIAAT, GAD67, vGAT expressions, and LC3 II/LC3 I ratio; increased p62 level and p-mTOR/mTOR ratio; and promoted cell apoptosis. Inhibition of mTOR reversed the effect of VB6 deficiency on cell autophagy. GABA activation or mTOR inhibition offset the role of VB6 deficiency in autism-like behaviors and hippocampal GABA expression. Collectively, VB6 deficiency induces autism-like behaviors in rats by regulating mTOR-mediated autophagy in the hippocampus.

Neurobehavioral sex-related differences in Nf1+/− mice: female show a “camouflaging”-type behavior

BackgroundNeurofibromatosis type 1 (NF1) is an inherited neurocutaneous disorder associated with neurodevelopmental disorders including autism spectrum disorder (ASD). This condition has been associated with an increase of gamma-aminobutyric acid (GABA) neurotransmission and, consequently, an excitation/inhibition imbalance associated with autistic-like behavior in both human and animal models. Here, we explored the influence of biological sex in the GABAergic system and behavioral alterations induced by the Nf1+/− mutation in a murine model.MethodsJuvenile male and female Nf1+/− mice and their wild-type (WT) littermates were used. Hippocampus size was assessed by conventional toluidine blue staining and structural magnetic resonance imaging (MRI). Hippocampal GABA and glutamate levels were determined by magnetic resonance spectroscopy (MRS), which was complemented by western blot for the GABA(A) receptor. Behavioral evaluation of on anxiety, memory, social communication, and repetitive behavior was performed.ResultsWe found that juvenile female Nf1+/− mice exhibited increased hippocampal GABA levels. Moreover, mutant female displays a more prominent anxious-like behavior together with better memory performance and social behavior. On the other hand, juvenile Nf1+/− male mice showed increased hippocampal volume and thickness, with a decrease in GABA(A) receptor levels. We observed that mutant males had higher tendency for repetitive behavior.ConclusionsOur results suggested a sexually dimorphic impact of Nf1+/− mutation in hippocampal neurochemistry, and autistic-like behaviors. For the first time, we identified a “camouflaging”-type behavior in females of an animal model of ASD, which masked their autistic traits. Accordingly, like observed in human disorder, in this animal model of ASD, females show larger anxiety levels but better executive functions and production of normative social patterns, together with an imbalance of inhibition/excitation ratio. Contrary, males have more externalizing disorders, such as hyperactivity and repetitive behaviors, with memory deficits. The ability of females to camouflage their autistic traits creates a phenotypic evaluation challenge that mimics the diagnosis difficulty observed in humans. Thus, we propose the study of the Nf1+/− mouse model to better understand the sexual dimorphisms of ASD phenotypes and to create better diagnostic tools.

Metabolomic profiling relates tianeptine effectiveness with hippocampal GABA, myo-inositol, cholesterol, and fatty acid metabolism restoration in socially isolated rats.

Discovering biomarkers of major depressive disorder (MDD) can give a deeper understanding of this mood disorder and improve the ability to screen for, diagnose, and treat MDD. In this study, metabolomics was used in unraveling metabolite fluctuations of MDD and drug outcome by creating specific metabolomic fingerprints. We report metabolomic patterns of change of the hippocampus of adult male Wistar rats following chronic social isolation (CSIS) (6weeks), an animal model of depression, and/or chronic tianeptine (Tian) treatment (10mgkg-1 per day) (lasting 3weeks of 6-week CSIS), monitored by using comprehensive GC × GC-MS. The comparative metabolomic analysis highlighted the role of gamma aminobutyric acid (GABA), iso-allocholate, and unsaturated fatty acid metabolism alterations following the CSIS, which was corroborated with moderate to strong negative Pearson's correlation of GABA, docosahexaenoic, 9-hexadecenoic acid, 5,8,11,14-eicosatetraynoic, and arachidonic acids with immobility behavior in the forced swim test. The antidepressant effect of Tian restored GABA levels, which was absent in Tian resilient rats. Tian decreased myo-inositol and increased TCA cycle intermediates, amino acids, and cholesterol and its metabolite. As key molecules of divergence between Tian effectiveness and resilience, metabolomics revealed myo-inositol, GABA, cholesterol, and its metabolite. A significant moderate positive correlation between myo-inositol and immobility was revealed. Tian probably acted by upregulating NMDAR's and α2 adrenergic receptors (AR) or norepinephrine transporter in both control and stressed animals. Metabolomics revealed several dysregulations underlying CSIS-induced depressive-like behavior and responsiveness to Tian, predominantly converging into NMDAR-mediated glutamate and myo-inositol signalization and GABA inhibitory pathways.

Altered hippocampal GR/KCC2 signaling mediates susceptibility to convulsion in male offspring following dexamethasone exposure during pregnancy in rats

Epidemiological research suggests that convulsions may have an intrauterine developmental origin related to the application of dexamethasone, an artificially synthesized glucocorticoid. Here, using a rat animal model of prenatal dexamethasone exposure (PDE) we confirm that PDE can cause susceptibility to convulsions in male offspring and explore the epigenetic programming mechanism underlying this effect related to intrauterine type 2 K+-Cl- cotransporter (KCC2). Wistar rats were injected with dexamethasone (0.2 mg/kg/d) subcutaneously during the gestational days (GD) 9–20 and part of the offspring was given lithium pilocarpine (LiPC) at postnatal week 10. Our results showed that male offspring of the PDE+LiPC group exhibited convulsions susceptibility, as well as increased hippocampal gamma-aminobutyric acid (GABA) and intracellular chloride ions level and decreased GABA receptor expression. The offspring also showed a decrease of hippocampal KCC2 H3K14ac levels and KCC2 expression. PDE male fetal rats (GD20) showed similar changes to male offspring after birth and exhibited an increased expression of glucocorticoid receptor (GR) and histone deacetylase type 2 (HDAC2). We observed effects consistent with those observed in PDE fetal rats following in vitro dexamethasone treatment of the fetal rat hippocampal neuron H19–7 cell line, and the effects could be reversed by treatment with a GR inhibitor (RU486) or HDAC2 inhibitor (romidepsin). Taken together, this study confirmed that PDE causes a reduction of H3K14ac levels in the KCC2 promoter region caused by activation of fetal hippocampal GR-HDAC2-KCC2 signaling. We proposed that this abnormal epigenetic modification is the mechanism underlying offspring convulsions susceptibility. CategoriesMechanism of toxicity.

FG7142 combined with restraint stress induces anxiogenic-like effects via downregulation gamma-aminobutyric acid type A receptor subunit alpha1 and 5-hydroxytryptamine 1A receptors expression in the hippocampus.

The existing anxiety animal models are susceptible to interference, and no single animal anxiety model can predict the future anxiolytic potential and profile of new putative anxiolytics. Therefore, to find a better anxiety animal model, we used FG7142, a nonselective benzodiazepine inverse agonist. This anxiety animal model was established by intraperitoneal injection of FG7142 combined with restraint stress. Adult male C57BL/6J mice (18-20 g) were randomly classified into five groups (n = 10 per group), namely the control, restraint stress, restraint stress + 10 mg/kg FG7142, restraint stress + 20 mg/kg FG7142, restraint stress +30 mg/kg FG7142. The impact on behavior was explored by elevated plus maze, and marble burying test, followed by immunohistochemistry and quantitative real-time PCR enabled the elucidation of the possible mechanism. Compared with the control group and restraint stress group, intraperitoneal injection of FG7142 combined with restraint stress model group was found to induce anxiogenic-like behavior in elevated plus maze and marble burying test. Moreover, relative to the control group, significantly increased expression of c-fos in the hippocampus and amygdala in the model group was evident, whereas the expression of gamma-aminobutyric acid type A receptor subunit alpha1 and 5-hydroxytryptamine receptor 1A mRNA was significantly decreased in the hippocampus. These results indicated that FG7142 combined with restraint stress is sufficient to induce anxiety, and its mechanism is associated with downregulation of hippocampal gamma-aminobutyric acid type A receptor subunit alpha1 and 5-hydroxytryptamine 1A receptors.

A role for GABA in the modulation of striatal and hippocampal systems under stress

Previous research has demonstrated that stress modulates the competitive interaction between the hippocampus and striatum, two structures known to be critically involved in motor sequence learning. These earlier investigations, however, have largely focused on blood oxygen-level dependent (BOLD) responses. No study to date has examined the link between stress, motor learning and levels of striatal and hippocampal gamma-aminobutyric acid (GABA). This knowledge gap is surprising given the known role of GABA in neuroplasticity subserving learning and memory. The current study thus examined: a) the effects of motor learning and stress on striatal and hippocampal GABA levels; and b) how learning- and stress-induced changes in GABA relate to the neural correlates of learning. To do so, fifty-three healthy young adults were exposed to a stressful or non-stressful control intervention before motor sequence learning. Striatal and hippocampal GABA levels were assessed at baseline and post-intervention/learning using magnetic resonance spectroscopy. Regression analyses indicated that stress modulated the link between striatal GABA levels and functional plasticity in both the hippocampus and striatum during learning as measured with fMRI. This study provides evidence for a role of GABA in the stress-induced modulation of striatal and hippocampal systems.

Investigation of the effect of REM sleep deprivation on epileptic seizures caused by pentylenetetrazole in mice

Aim: To investigate whether different periods of rapid eye movement sleep deprivation (REM SD) contribute to seizure susceptibility, hippocampal oxidative status and balance of inhibition-excitation in the acute epilepsy model. Methods: REM SD was performed using the modified multiple platforms method on adult male BALB/c mice. Pentylentetrazol (PTZ) was injected to induce seizures and hippocampal total antioxidant status (TAS), total oxidant status (TOS), gamma aminobutyric acid (GABA), and glutamate levels were measured using the ELISA method. Results: PTZ-induced seizures following 8 h and 72 h REM SD significantly reduced the hippocampal TAS levels, but did not affect the TOS levels. In REM SD groups, especially after 8 hours of REM sleep loss, there was a significant increase in glutamate in PTZ induction. The hippocampal GABA levels were increased by PTZ-induced seizures after 72 h REM SD. PTZ- induction after 8 hours of RAM SD leads to a significant increase in the seizure duration. Conclusion: It can be speculated that the REM SD can contribute to seizure susceptibility by changing the oxidant-antioxidant balance and excitatory and inhibitory tone in the hippocampus.

Minocycline ameliorates anxiety-related self-grooming behaviors and alters hippocampal neuroinflammation, GABA and serum cholesterol levels in female Sprague-Dawley rats subjected to chronic unpredictable mild stress

Neuroinflammation induced by stress results in aberrant neurotransmission and dyslipidemia, which can trigger depression- and anxiety-like behaviors. Gamma-aminobutyric acid (GABA) and cholesterol play a crucial role in anxiety-like states, including self-grooming - a common stress-evoked rodent behavior. However, the interaction between neuroinflammation, GABA and cholesterol under stress, and their effects on grooming, remain unclear. Here, we utilize the chronic unpredictable mild stress (CUMS) rat cohort used previously in our Zhang et al. (2019) study, to examine whether CUMS affects grooming behavior, and whether minocycline, a microglia antagonist, can correct these behavioral deficits, accompanied by altering hippocampal neuroinflammation, GABA and serum cholesterol levels. Female Sprague-Dawley rats underwent a 6-week CUMS and received daily minocycline (40 mg/kg, i.p.) during this period, followed by behavioral testing in the open field test. Serum cholesterol, inflammatory cytokines and GABA levels in hippocampus were assayed by ELISA. CUMS significantly decreased locomotion, rearing, central zone entries and time spent in the open field center compared to unstressed controls. CUMS also strongly affected self-grooming behaviors, increasing the frequency of grooming episodes, the number of transitions, interruptions and individual elements of various grooming phases. However, these CUMS-induced behavioral abnormalities were corrected by minocycline. Likewise, CUMS elevated total serum cholesterol and lowered serum high-density lipoprotein cholesterol, whereas minocycline ameliorated these responses. CUMS also lowered hippocampal GABA, whereas minocycline normalized CUMS-induced GABA in the hippocampus. We also found significant correlations between neuroinflammation and GABA, neuroinflammation and cholesterol, GABA and grooming, as well as cholesterol and grooming measures, further implicating stress-evoked neuroinflammation, GABA and cholesterol in the regulation of complex rodent behaviors. In summary, minocycline ameliorated CUMS-induced aberrant self-grooming behaviors in rats by altering hippocampal neuroinflammation, GABA and serum cholesterol levels.

Altered hippocampal GABA and glutamate levels and uncoupling from functional connectivity in multiple sclerosis.

There is growing evidence for dysfunctional glutamatergic excitation and/or gamma-aminobutyric acid (GABA)ergic inhibition in patients with multiple sclerosis (MS). Cognitive impairment may occur during the early stages of MS and hippocampal abnormalities have been suggested as biomarkers. However, researchers have not clearly determined whether changes in hippocampal GABA and glutamate (Glu) levels are associated with cognitive impairment and aberrant neural activity in patients with MS. We used magnetic resonance spectroscopy to measure GABA+ and Glu levels in the left hippocampal region of 29 patients with relapsing-remitting MS and 29 healthy controls (HCs). Resting-state functional connectivity (FC) with the hippocampus was also examined. Compared to HCs, patients exhibited significantly lower GABA+ and Glu levels, which were associated with verbal and visuospatial memory deficits, respectively. Patients also showed decreased FC strengths between the hippocampus and several cortical regions, which are located within the default mode network. Moreover, hippocampal GABA+ levels and Glu/GABA+ ratios correlated with the FC strengths in HCs but not in patients with MS. This study describes a novel method for investigating the complex relationships among excitatory/inhibitory neurotransmitters, brain connectivity and cognition in health and disease. Strategies that modulate Glu and GABA neurotransmission may represent new therapeutic treatments for patients with MS.

Impact of the Alpha-7 Nicotinic Acetylcholine Receptor on Long-Term Potentiation within the Hippocampus: Implications in Schizophrenia

Schizophrenia is a debilitating psychiatric disorder associated with progressive cognitive decline across perception, social and affective processes, and memory. The alpha-7 nicotinic acetylcholine receptor (a7 nAChR) is implicated in the cognitive pathophysiology of schizophrenia. This receptor specifically affects memory by facilitating long-term potentiation (LTP) within the hippocampus. This article reviews the role of the a7 nAChR in enhancement of LTP via its impact on hippocampal gamma-aminobutyric acid (GABA)-ergic and glutamatergic pathways. Future therapeutic implications of a7 nAChR in improvement of cognitive impairment in schizophrenia are also discussed. [ Psychiatr Ann. 2018;48(7):345–348.]

Dexmedetomidine and propofol sedation requirements in an autistic rat model

BackgroundAutism is a challenging neurodevelopmental disorder. Previous clinical observations have suggested altered sedation requirements for children with autism. Our study aimed to test this observation experimentally in an animal model and to explore its possible mechanisms.MethodsEight adult pregnant female Sprague-Dawley rats were randomly divided into two groups. Four were injected with intraperitoneal sodium valproate on gestational day 12 and four were injected with normal saline. On postnatal day 28, the newborn male rats were subjected to the open-field test to confirm autistic features. Each rat was injected intraperitoneally with a single dose of propofol (50 mg/kg) or dexmedetomidine (0.2 mg/kg). The times to loss of righting reflex (LORR) and to return of righting reflex (RORR) were recorded. On the following day, all rats were re-sedated and underwent electroencephalography (EEG). Thereafter, the rats were euthanized and their hippocampal gamma-aminobutyric acid type A (GABAA) and glutamate N-methyl-D-aspartate (NMDA) receptor gene expressions were assessed.ResultsAutistic rats showed significantly longer LORR times and shorter RORR times than did the controls (median LORR times: 12.0 versus 5.0 min for dexmedetomidine and 22.0 versus 8.0 min for propofol; P < 0.05). EEG showed a low-frequency, high-amplitude wave pattern 2 min after LORR in the control rats. Autistic rats showed a high-frequency, low-amplitude awake pattern. Hippocampal GABAA receptor gene expression was significantly lower and NMDA gene expression was greater in autistic rats.ConclusionsThis study supports the clinical observations of increased anesthetic sedative requirements in children with autism and our biochemical analyses using GABAA and glutamate receptor gene expression highlight possible underlying mechanisms.

Sex- and age-specific modulation of brain GABA levels in a mouse model of Alzheimer's disease

Age and sex are risk factors of Alzheimer's disease (AD). Among the neurotransmitter systems, gamma-aminobutyric acid (GABA) has been implicated in AD pathogenesis but the relevance of sex-specific GABAergic dysfunction during AD progression remains unknown. In the present study, we utilized state-of-the-art high-resolution magic angle spinning nuclear magnetic resonance to systematically monitor the brain region-, age-, and sex-specific modulation of GABA levels in wild-type and Tg2576 mice with amyloid pathology. In addition, we followed the possible role of reactive astrocytes in sex-specific GABA modulation. In female Tg2576 mice, hippocampal GABA levels were significantly elevated, along with higher number of reactive astrocytes and amyloid deposition. The elevated GABA was found to be produced via the monoamine oxidase-B route from putrescine in reactive astrocytes, more substantially in female than male mice, thus suggesting a role of astrocytes in memory impairment and sex-related differences in AD. Our results paint a coherent model of memory impairment in AD and signify that dynamic changes in regional GABA may be at the root of marked sex disparities observed in AD.

G Protein-Gated K+ Channel Ablation in Forebrain Pyramidal Neurons Selectively Impairs Fear Learning

BackgroundCognitive dysfunction occurs in many debilitating conditions including Alzheimer’s disease, Down syndrome, schizophrenia, and mood disorders. The dorsal hippocampus is a critical locus of cognitive processes linked to spatial and contextual learning. G protein-gated inwardly rectifying potassium ion (GIRK/Kir3) channels, which mediate the postsynaptic inhibitory effect of many neurotransmitters, have been implicated in hippocampal-dependent cognition. Available evidence, however, derives primarily from constitutive gain-of-function models that lack cellular specificity. MethodsWe used constitutive and neuron-specific gene ablation models targeting an integral subunit of neuronal GIRK channels (GIRK2) to probe the impact of GIRK channels on associative learning and memory. ResultsConstitutive Girk2–/– mice exhibited a striking deficit in hippocampal-dependent (contextual) and hippocampal-independent (cue) fear conditioning. Mice lacking GIRK2 in gamma-aminobutyric acid neurons (GAD-Cre:Girk2flox/flox mice) exhibited a clear deficit in GIRK-dependent signaling in dorsal hippocampal gamma-aminobutyric acid neurons but no evident behavioral phenotype. Mice lacking GIRK2 in forebrain pyramidal neurons (CaMKII-Cre(+):Girk2flox/flox mice) exhibited diminished GIRK-dependent signaling in dorsal, but not ventral, hippocampal pyramidal neurons. CaMKII-Cre(+):Girk2flox/flox mice also displayed a selective impairment in contextual fear conditioning, as both cue fear and spatial learning were intact in these mice. Finally, loss of GIRK2 in forebrain pyramidal neurons correlated with enhanced long-term depression and blunted depotentiation of long-term potentiation at the Schaffer collateral/cornu ammonis 1 synapse in the dorsal hippocampus. ConclusionsOur data suggest that GIRK channels in dorsal hippocampal pyramidal neurons are necessary for normal learning involving aversive stimuli and support the contention that dysregulation of GIRK-dependent signaling may underlie cognitive dysfunction in some disorders.

Hippocampal orexin receptors inactivation reduces PTZ induced seizures of male rats

IntroductionOrexin has been shown to be involved in a number of physiological and behavioral processes including, feeding and metabolism, reward, nociception, and anxiety. Furthermore, orexin can cause increased neuronal excitability that gives rise to epileptic activity. The distribution of orexin receptor expression in the hippocampus, suggests a possible importance of orexin in the control of seizures in the temporal lobe epilepsy. Therefore, in this study, the effect of hippocampal orexin 1 and 2 receptors on seizure and glutamate and GABA (gamma-aminobutyric acid) contents was explored. Materials and methodsOrexin 1 receptor (OX1R) antagonist (SB) and OX2R antagonist (TCS) were administrated bilaterally through separate cannulae into both hippocampi. Behavioral convulsions were provoked by intravenous pentylenetetrazol (PTZ) application model. The amount of total hippocampal glutamate and GABA contents was then measured by a biochemical method. ResultsSB (50nmol) infusion reduced seizure stage, duration and decreased glutamate while GABA content was increased. SB (200nmol) also reduced seizure stage, duration and glutamate content, without change of GABA content. TCS (20nmol) infusion reduced seizure stage and duration without concomitant change in glutamate and GABA contents. Further, TCS (40nmol) did neither affect the seizure nor the GABA, while decreased glutamate content. Co-administration of SB (50nmol) with TCS (40nmol) and also SB (200nmol) with TCS (40nmol) reduced seizure stage, duration and glutamate, but increased GABA content. ConclusionIt is concluded that OX1R and OX2R antagonists reduce convulsive intensity, partially through alterations of hippocampal glutamate and GABA contents.

Parvalbumin and neuropeptide Y expressing hippocampal GABA-ergic inhibitory interneuron numbers decline in a model of Gulf War illness.

Cognitive dysfunction is amongst the most conspicuous symptoms in Gulf War illness (GWI). Combined exposure to the nerve gas antidote pyridostigmine bromide (PB), pesticides and stress during the Persian Gulf War-1 (PGW-1) are presumed to be among the major causes of GWI. Indeed, our recent studies in rat models have shown that exposure to GWI-related (GWIR) chemicals and mild stress for 4 weeks engenders cognitive impairments accompanied with several detrimental changes in the hippocampus. In this study, we tested whether reduced numbers of hippocampal gamma-amino butyric acid (GABA)-ergic interneurons are among the pathological changes induced by GWIR-chemicals and stress. Animals were exposed to low doses of GWIR-chemicals and mild stress for 4 weeks. Three months after this exposure, subpopulations of GABA-ergic interneurons expressing the calcium binding protein parvalbumin (PV), the neuropeptide Y (NPY) and somatostatin (SS) in the hippocampus were stereologically quantified. Animals exposed to GWIR-chemicals and stress for 4 weeks displayed reduced numbers of PV-expressing GABA-ergic interneurons in the dentate gyrus and NPY-expressing interneurons in the CA1 and CA3 subfields. However, no changes in SS+ interneuron population were observed in the hippocampus. Furthermore, GABA-ergic interneuron deficiency in these animals was associated with greatly diminished hippocampus neurogenesis. Because PV+ and NPY+ interneurons play roles in maintaining normal cognitive function and neurogenesis, and controlling the activity of excitatory neurons in the hippocampus, reduced numbers of these interneurons may be one of the major causes of cognitive dysfunction and reduced neurogenesis observed in GWI. Hence, strategies that improve inhibitory neurotransmission in the hippocampus may prove beneficial for reversing cognitive dysfunction in GWI.

Different effects of etomidate and propofol on memory in immature rats

This study is to investigate the effects of etomidate and propofol on memory and possible involved mechanisms using immature rats. Forty-eight rats randomly received intraperitoneal injection of 5 mg/kg etomidate ( n = 16), 50 mg/kg propofol ( n = 16) or normal saline (control, n = 16). Three hours after awakening, memory was assessed by Y-maze test using 10 rats in each drug group. Gamma-aminobutyric acid (GABA) content in hippocampal tissue was measured using six rats in each group. Etomidate group had more total reaction time (TRT) compared with the control group in Y-maze test ( p < 0.05). No other difference between these two groups was observed. Propofol group had less number of correct response ( p < 0.01) and more TRT ( p < 0.05) in Y-maze test, as well as more GABA concentration detected in hippocampal tissue ( p < 0.01) than the control group. Propofol group also showed less number of correct response ( p < 0.05) and more hippocampal GABA concentration ( p < 0.01) compared with etomidate group. Etomidate does not show significant effects on memory in rat and further investigation is required. Propofol can affect memory in rat possibly via increasing the synthesis and/or secretion of GABA as one of the factors.

Effects of ghrelin on seizures in rats and expression of the gamma-aminobutyric acid

Objective To explore the effects of ghrelin on hippocampal neurons after seizures induced by kainic acid (KA),and to investigate the correlation between Ghrelin and the expression changes in hippocampal gamma-aminobutyric acid (GABA) in rats.Methods A model of KA-induced epilepsy in rats was established,and intervened with exogenous ghrelin.Ethological and morphological changes were observed.Hematoxylin and eosin (HE) staining and Nissl staining were used to examine the antiepileptic effects.Immunofluorescence was used to detect the expression of GABA.Results After KA injection,the rats began to seizure after a latent period.The latency time in Ghrelin treatment group ( 12.3 ± 3.5 ) min was lengthened significantly as compared with epilepsy group [ ( 8.7 ± 1.2) min,P ＜ 0.05 ].Moreover,tonic-clonic duration in Ghrelin treatment group ( 10.8 ± 1.4) min was significantly shorter than in epilepsy group ( 15.2 ± 2.7 ) min,P ＜ 0.05 ].There was an obviously morphological changes in hippocampal neurons of epileptic rats with severe neurons loss,and statistical analysis revealed that the nerve cell apoptosis and loss in Ghrelin treatment group were decreased as compared with epilepsy group at different time points (P ＜ 0.05).Immunofluorescence indicated that the number of GABA neurons was continued to decrease with time as compared with control group after injection of KA into the rat hippocampus within 24 h.And its decrease trend was more gentle after injecting Ghrelin ( P ＜ 0.05 ).Conclusion Our results implied that Ghrelin had protective effects on hippocampal neurons by influencing the expression of GABA in central nervous system. Key words: Ghrelin; Epilepsy; Gamma-aminobutyric acid; Kainic acid

Downregulation of Hippocampal GABA after Hypoxia-Induced Seizures in Neonatal Rats

This study aims to determine the expression of Gamma-aminobutyric acid (GABA) following hypoxia in neonatal rats and explore how it may increase susceptibility to epilepsy later in life. A modified model of neonatal hypoxia-induced epileptic susceptibility was simulated by 17 min of hypoxia (5% O(2) and 95% N(2)) in postnatal day (P) 10 rats. Hippocampal glutamate decarboxylase (GAD) and parvalbumin (PV) during the development with or without hypoxia were examined using immunohistochemistry. No detectable neuronal loss was observed in the hippocampus either immediately or 14 days after hypoxia. During the development GAD- and PV-immunoreactivity increased substantially during P 11-13 and reached mature expression in the control rats, and decreased significantly at different time points except for a transient increase during P 11-13 in the hypoxic groups. Our study indicates that downregulation of hippocampal GABA after hypoxia-induced seizures in neonatal rats may contribute to higher epileptic susceptibility in later life.

Zinc and glutamine improve brain development in suckling mice subjected to early postnatal malnutrition

Objective The effect of zinc and glutamine on brain development was investigated during the lactation period in Swiss mice. Methods Malnutrition was induced by clustering the litter size from 6–7 pups/dam (nourished control) to 12–14 pups/dam (undernourished control) following birth. Undernourished groups received daily supplementation with glutamine by subcutaneous injections starting at day 2 and continuing until day 14. Glutamine (100 mM, 40–80 μL) was used for morphological and behavioral studies. Zinc acetate was added in the drinking water (500 mg/L) to the lactating dams. Synaptophysin and myelin basic protein brain expressions were evaluated by immunoblot. Zinc serum and brain levels and hippocampal neurotransmitters were also evaluated. Results Zinc with or without glutamine improved weight gain as compared to untreated, undernourished controls. In addition, zinc supplementation improved cliff avoidance and head position during swim behaviors especially on days 9 and 10. Using design-based stereological methods, we found a significant increase in the volume of CA1 neuronal cells in undernourished control mice, which was not seen in mice receiving zinc or glutamine alone or in combination. Undernourished mice given glutamine showed increased CA1 layer volume as compared with the other groups, consistent with the trend toward increased number of neurons. Brain zinc levels were increased in the nourished and undernourished-glutamine treated mice as compared to the undernourished controls on day 7. Undernourished glutamine-treated mice showed increased hippocampal gamma-aminobutyric acid and synaptophysin levels on day 14. Conclusion We conclude that glutamine or zinc protects against malnutrition-induced brain developmental impairments.