Elsevier

Epilepsy Research

Volume 71, Issue 1, September 2006, Pages 47-53
Epilepsy Research

Developmental changes in the expression of GABAA receptor alpha 1 and gamma 2 subunits in human temporal lobe, hippocampus and basal ganglia: An implication for consideration on age-related epilepsy

https://doi.org/10.1016/j.eplepsyres.2006.05.019Get rights and content

Abstract

Mutations of genes encoding GABAA receptor alpha 1 (GABARA1) and gamma 2 subunit (GABARG2) are associated with age-dependent epilepsy. The development of the subunits expression may be related to the age-dependency of epilepsy. Nevertheless, developmental and spatial changes in expression of GABAA receptors have not been examined in the human brain. Using immunohistochemistry, we examined the development of GABARA1 and GABARG2 in the human temporal lobe, hippocampus and basal ganglia in specimens obtained from 21 fetuses/subjects who died aged 22 gestation weeks (GW) to 75 years. Unique developmental changes of GABARA1 and GABARG2 were recorded in each region. In hippocampal pyramidal cells, GABARA1 was already found from 22 GW mainly on CA2-3, whereas GABARG2 was expressed later than GABARA1 predominantly in CA3. In the temporal cortex, both subunits appeared in the pyramidal cells layer from 22 GW, while GABARA1 and GABARG2 expression was increased from 29 to 38 GW, respectively. Furthermore, transient increase of GABARA1 was detected in the granular cell layer of the hippocampus from 29 GW to 4 months, in the cortical pyramidal cell layer from 29 to 40 GW, and in the putamen from birth to 5 years of age. Thus gradual or transient increase of GABARA1 and GABARG2 was found in every region at different age. These developmental changes in the expression of these subunits may contribute to the age dependency in some epilepsy syndromes where deficiency of GABARA1 and GABARG2 is involved.

Introduction

The mechanism of age-dependency of epilepsy is poorly understood. Several point mutations in the subunits of GABAA receptor have been recently found to be linked to various age-dependent epilepsy syndromes (Baulac et al., 2001, Wallace et al., 2001, Cossette et al., 2002, Harkin et al., 2002). In this regard, the disruption of GABA-mediated pathways is known to be associated with epilepsy (Olsen et al., 1999).

GABAA receptor is a ligand-gated ion channel and Cl ion currents generated by GABA, a physiological ligand, are associated with the main inhibitory system in the central nervous system (Barnard et al., 1998). GABAA receptor also has binding sites of benzodiazepines. GABAA receptor is a hetero-pentamer, which consists of various subunits such as α, β, γ, δ, ɛ, θ and π. However, the main subunits in the brain are two of α1, two of β2 and one of γ2 subunit (Sieghart et al., 1999).

Several different mutations in the gene that encodes the GABAA receptor γ2-subunit (GABARG2), have been recently identified in four families with generalized epilepsy syndromes associated with febrile seizures (FS), including generalized epilepsy with febrile seizures plus (GEFS+) and classical childhood absence epilepsy (CAE) (Baulac et al., 2001, Wallace et al., 2001, Harkin et al., 2002, Kananura et al., 2002). Both share a unique seizure phenotype referred to as febrile seizures plus that consists of FS extending beyond 6 years of age and/or subsequent frequent afebrile seizures. Furthermore, a truncation mutation of GABRG2 was reported to be associated with severe myoclonic epilepsy of infancy (SMEI), of which seizure phenotype usually starts in infancy (Singh et al., 2001).

In addition, a mutation of the GABAA receptor α1-subunit (GABARA1) was found in affected individuals with autosomal dominant juvenile myoclonic epilepsy (ADJME) in a French-Canadian family. Functional studies of the mutant receptor expressed in Xenopus laevis oocytes show that the mutation results in decreased GABA-activated currents (Cossette et al., 2002).

Thus, epilepsy syndromes in which mutations of GABAA receptor have so far been identified are all age-dependent and thus development of GABAA receptor may be closely linked to such age-dependency. In fact, it has been shown in the rat brain that the expression patterns of mRNAs of different subunits change with development (Laurie et al., 1992). Nevertheless, development of human GABAA receptor per se has not been studied in detail.

The purpose of this study was to analyze the developmental change in GABARA1 and GABARG2, both of which are associated with age-dependent epilepsy syndrome as mentioned above.

Section snippets

Human tissue specimen

Twenty human brains obtained from fetuses/subjects who died aged 22 gestation weeks (GW) to 75 years were used for immunohistochemical studies. Informed consent for postmortem examination was given in writing by the patients or their family representatives. The causes of death were spontaneous abortion, cardiomyopathy, congenital heart disease, or acute lymphocytic leukemia without CNS involvement in fetuses, infants and children, and squamous cell carcinoma without CNS involvement, or liver

Results

The immunoreactivities for GABARA1 and GABARG2 in the developing human hippocampus, temporal lobe and basal ganglia are described in Table 1, Table 2. In the hippocampus, a few GABARA1 immunoreactive neuronal somas were seen in the dentate gyrus and subiculum from 22 GW. GABARA1 expression gradually increased with age and marked GAGARA1 immunoreactivity was noted in the dentate gyrus from 29 GW to 4 months of age. However, it decreased subsequently during childhood but increased again during

Discussion

In the human brain, we found developmental changes in GABARA1 and GABARG2 immunoreactivities in the temporal lobe, hippocampus and basal ganglia. In hippocampus, both subunits were markedly expressed mainly in CA2-3. The appearance of GABARG2 occurred later than that of GABARA1 in the hippocampus. In the temporal cortex, GABARA1 appeared in the pyramidal cell layer from early fetal period, while GABARG2 was delayed to become moderate from 38 GW. Marked GABARA1 was noted in pyramidal cells of

Acknowledgements

This study was supported in part by grants from the Ministry of Health, Labor and Welfare, and the Ministry of Education, Science and Culture of Japan.

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