ABSTRACT
Objective:To investigate the genetic association of single nucleotide polymorphisms (SNPs) in gamma-aminobutyric acid type A (GABAA) receptor genes cluster on chromosome 15q12 with autism in Chinese Han population.Methods:Totally 502 autism trios of Chinese Han ethnicity (including 502 autism individuals and 1004 healthy biological parents) were selected.All children met the autism diagnosis of Diagnostic and Statistical Manual of Mental Disorders,Fourth edition (DSM-Ⅳ).Genotyping for 15 selected tag SNPs in three GABAA receptor genes (GABRB3,GABRA5,and GABRG3) was performed using Agena Bioscience MassARRAY platform.The family-based association test for 15 tag SNPs was performed to compare the transmitted frequency of al leles of heterozygous genotypes from parents to offspring in autism trios.Results:The C allele of rs7180500 in GABRG3 and the A allele of rs4906902 in GABRB3 exhibited the preferential transmission from parents to affected offspring (Z =3.573,P ＜0.001;Z =3.141,P =0.002),and the association was significant after Bonferroni correction.Conclusion:It suggests that GABRG3 and GABRB3 which located in chromosome 15q12 might be susceptibility genes in Chinese Han population.
ABSTRACT
The sustained tonic currents (I(tonic)) generated by γ-aminobutyric acid A receptors (GABA(A)Rs) are implicated in diverse age-dependent brain functions. While various mechanisms regulating I(tonic) in the hippocampus are known, their combined role in I(tonic) regulation is not well understood in different age groups. In this study, we demonstrated that a developmental increase in GABA transporter (GAT) expression, combined with gradual decrease in GABA(A)R α₅ subunit, resulted in various I(tonic) in the dentate gyrus granule cells (DGGCs) of preadolescent rats. Both GAT-1 and GAT-3 expression gradually increased at infantile (P₆₋₈ and P₁₃₋₁₅) and juvenile (P₂₀₋₂₂ and P₂₇₋₂₉) stages, with stabilization observed thereafter in adolescents (P₃₄₋₃₆) and young adults (P₄₁₋₄₃). I(tonic) facilitation of a selective GAT-1 blocker (NO-711) was significantly less at P₆₋₈ than after P₁₃₋₁₅. The facilitation of I(tonic) by SNAP-5114, a GAT-3 inhibitor, was negligible in the absence of exogenous GABA at all tested ages. In contrast, I(tonic) in the presence of a nonselective GAT blocker (nipecotic acid, NPA) gradually decreased with age during the preadolescent period, which was mimicked by I(tonic) changes in the presence of exogenous GABA. I(tonic) sensitivity to L-655,708, a GABA(A)R α₅ subunit inverse agonist, gradually decreased during the preadolescent period in the presence of NPA or exogenous GABA. Finally, Western blot analysis showed that the expression of the GABA(A)R α₅ subunit in the dentate gyrus gradually decreased with age. Collectively, our results suggested that the I(tonic) regulation of altered GATs is under the final tune of GABA(A)R α₅ subunit activation in DGGCs at different ages.
Subject(s)
Adolescent , Animals , Humans , Rats , Young Adult , Blotting, Western , Brain , Dentate Gyrus , gamma-Aminobutyric Acid , HippocampusABSTRACT
Perillae Herba has been traditionally used for the sedation in the oriental countries. Therefore, this study was conducted to determine whether Perillae Herba ethanol extract (PHEE) enhances pentobarbital-induced sleeping behaviors in animals. In addition, the possible mechanisms are demonstrated. PHEE (12.5, 25 and 50 mg/kg. p.o.) reduced the locomotor activity in mice. PHEE reduced sleep latency and augmented the total sleep time in pentobarbital (42 mg/kg, i.p.)-induced sleep in mice. Furthermore, the number of sleeping mice treated with sub-hypnotic pentobarbital (28 mg/kg, i.p.) increased. PHEE (50 mg/kg. p.o.) decreased the sleep/wake cycles and wakefulness, and increased total sleeping time and NREM sleep in electroencephalogram (EEG) of rats. In addition, PHEE (0.1, 1.0 and 10 µg/ml) increased the intracellular Cl⁻ level through the GABA receptors in the hypothalamus of rats. Moreover, the protein of glutamate decarboxylase (GAD) was overexpressed by PFEE. It was found that PHEE enhanced pentobarbital-induced sleeping behaviors through GABA(A)-ergic transmissions.
Subject(s)
Animals , Mice , Rats , Electroencephalography , Ethanol , Eye Movements , gamma-Aminobutyric Acid , Glutamate Decarboxylase , Hypothalamus , Motor Activity , Pentobarbital , Perilla , Receptors, GABA , WakefulnessABSTRACT
Resumen En esta investigación se evaluaron los efectos de la administración sistémica del antagonista GABAA bicuculina sobre los efectos del agonista 5-HT1A 8-OH-DPAT en las propiedades discriminativas de la anfetamina (ANF) utilizando el condicionamiento de aversión a los sabores. Los resultados mostraron que ni el 8-OH-DPAT, ni la bicuculina, sustituyeron la señal discriminativa de la ANF. Sin embargo, la administración del 8-OH-DPAT disminuyó la señal discriminativa de la ANF, y la administración de la bicuculina, previa a la administración del 8-OH-DPAT más una dosis de ANF, previno el efecto del 8-OH-DPAT sobre la señal discriminativa de la ANF. Estos datos apoyan la hipótesis de que las conductas relacionadas con la adicción a las drogas, como la ANF, involucran diferentes sistemas de neurotransmisión como la DA, la 5-HT y el GABA.
Abstract In this research, the effects of systemic administration of the GABAA receptor antagonist bicuculline on the effects of 5-HT1A receptor agonist 8-OH-DPAT on the discriminative properties of the AMPH using the conditioned taste aversion procedure were evaluated. The results showed that neither 8-OH-DPAT nor bicuculline administration did not substitute for AMPH. However, the 8-OH-DPAT administration decreased the discriminative signal of AMPH and the bicuculline administration, prior to the 8-OH-DPAT administration plus a dose of AMPH prevented the effect of the 8-OH-DPAT on discriminative signal of AMPH. These data support the hypothesis that addiction-related behaviors of drugs such as AMPH involve several neurotransmitter systems such as DA, 5-HT and GABA.
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Rhynchophylline (RP) is a major tetracyclic oxindole alkaloid of Uncariae Ramulus et Uncus which has been used to treat hypertension, seizures, pain and anxiety in the oriental countries. A recent report revealed that RP attenuated ischemia-induced neuronal damage and kainite-induced convulsions in animals. This study was performed to investigate whether RP enhances pentobarbital-induced sleep behaviors and modulates sleep architecture in mice. Locomotor activity was significantly inhibited by RP at 0.25 and 0.5 mg/kg, similar to 2 mg/kg diazepam (a benzodiazepine agonist) in mice. RP shortened sleep latency and increased total sleep time in a dose-dependent manner when administrated with pentobarbital (42 mg/kg, i.p.). RP also increased the number of sleeping mice and total sleep time by concomitant administration with the sub-hypnotic dosage of pentobarbital (28mg/kg, i.p.). On the other hand, RP (0.25mg/kg, p.o.) itself significantly inhibited sleep-wake cycles, prolonged total sleep time, and rapid eye movement in rats. In addition, RP also increased chloride influx in the primary cultured hypothalamic neuronal cells. In addition, we found that glutamic acid decarboxylase (GAD(65/67)) was activated by RP. In conclusion, RP augments pentobarbital-induced sleeping behaviors, and can be a candidate for treating insomnia.
Subject(s)
Animals , Mice , Rats , Anxiety , Benzodiazepines , Diazepam , Electroencephalography , Glutamate Decarboxylase , Hand , Hypertension , Motor Activity , Neurons , Pentobarbital , Rodentia , Seizures , Sleep Initiation and Maintenance Disorders , Sleep, REM , UncariaABSTRACT
γ-aminobutyric acid A(GABAA)receptor is one of the ligand-gated ion channel receptors expressing widely in the brain. As the major inhibitory neurotransmitter receptor, GABAA receptor is involved in the regulation of many physiological mechanisms. Imbalance expression of the receptor may lead to neuropsychiatric disorders such as schizophrenia,depression, epilepsy,post-traumatic stress disorder (PTSD) syndrome,neurofibromatosis type 1 and fragile X syndrome. Clinically classic benzodiazepines acting on GABAA receptor can be used for the auxiliary treatment of various neuropsychiatric disorders,which supports the potential therapeutic value of GABAA receptor for these diseases. The paper describes the molecular structure and subtypes of GABAA receptor and further reviews the progress in the link between GABAA receptor and neuropsychiatric disorders in order to provide a new target for the drug therapy development of neuropsychiatric disorders.
ABSTRACT
γ-aminobutyric acid A (GABAA) receptor is one of the ligand-gated ion channel receptors expressing widely in the brain. As the major inhibitory neurotransmitter receptor, GABAA receptor is involved in the regulation of many physiological mechanisms. Imbalance expression of the receptor may lead to neuropsychiatric disorders such as schizophrenia, depression, epilepsy, post-traumatic stress disorder (PTSD) syndrome, neurofibromatosis type 1 and fragile X syndrome. Clinically classic benzodiazepines acting on GABAA receptor can be used for the auxiliary treatment of various neuropsychiatric disorders, which supports the potential therapeutic value of GABAA receptor for these diseases. The paper describes the molecular structure and subtypes of GABAA receptor and further reviews the progress in the link between GABAA receptor and neuropsychiatric disorders in order to provide a new target for the drug therapy development of neuropsychiatric disorders.
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Fragile X syndrome is a common cause of inherit mental retardation,GABAA receptors are the major inhibitory neurotransmitter receptros in the mammalian central nervous system, implicated in anxiety,depression, epilepsy, sleeping problem, learning and memory, and so on. Several researches indicated that the GABAergic system, in particular the GABAA receptors might be related to the phenotype of fragile X syndrome. An altered expression of certain subunits of the GABAA receptors may cause the neurological and behavioural changes of the fragile X syndrome. Therefore,the GABAA receptors can be a novel therapeutic target for treatment of fragile X syndrome.
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The immature brain differs from the adult brain in its susceptibility to seizures, seizure characteristics, and responses to antiepileptic drugs. Gamma(gamma)-aminobutyric acid(GABA) is the predominant inhibitory neurotransmitter in the adult brain. GABA exerts its main action through GABAA receptors, which are coupled to a ligand-gated chloride channel. The receptor protein is a pentameric structure composed of multiple subunits of different families and isoforms. The subunit combinations vary in different brain regions and cell types and determine the functional and pharmacological properties of the receptor. The molecular composition of GABAA receptors is developmentally regulated with associated changes in functional properties. In the developing brain, the delayed onset of functional GABAergic inhibition, and the overabundance of excitatory receptors make the immature brain quite susceptible to seizures. Recurrent seizures in early-life may contribute to seizure susceptibility and epileptogenesis, although the pattern of seizure-induced injury is age-related. The changes of GABAA receptors expression in tetanus toxin-induced seizure model in immature rat hippocampus are different from human temporal lobe epilpsy and experimental model in adult rat. These changes in the immature brain may reflect the induction of compensatory or homeostatic neuronal processes.
Subject(s)
Adult , Animals , Humans , Rats , Anticonvulsants , Brain , Chloride Channels , gamma-Aminobutyric Acid , Hippocampus , Models, Theoretical , Neurons , Neurotransmitter Agents , Protein Isoforms , Seizures , Temporal Lobe , TetanusABSTRACT
AIM: To investigate the modification of GABAA receptor subunits in audiogenic seizure rat cortex and hippocampus when rendered tolerant to clobazam. METHODS: Rats were administrated with clobazam for two weeks, resulting in tolerance to clobazam. GABAA receptor subunit α1, α3, α5, γ2L and γ2S were assayed using quantitative competitive RT-PCR in rat FrPaM and hippocampus. RESULTS: In FrPaM, the content of mRNA encoding for α1, γ2L and γ2S were all significantly decreased (27%, 43% and 37% respectively), whereas that of α5 was significantly increased (73%) compared with the control. In hippocampus, α1, γ2L, and γ2S mRNA content was significantly decreased (28%, 32% and 31% respectively). CONCLUSION: The accomodated change in GABAA receptor subunit α1, α5, γ2L and γ2S in FrPaM and hippocampus may be associated with the mechanism for tolerance to clobazam in audiogenic seizure rat.
ABSTRACT
In addition to modulation by a variety of structurally diverse agents that act allosteri-cally via distinct binding sites on the receptor complexes , there is another outstanding characteristic of the GABAA receptors: they are modulated by multiple endogenous agents. Well known examples include Ca2+ , adenosine triphosphate (ATP) , protein kinase A (PKA), protein kinase C(PKC), ty-ros ine kinase (TK) and calmodulin-dependent protein kinase II (CaMK II ). Intracellular modulation of GABAA receptor function may have profound effects on the control of neuronal excitation.