Alternative splicing isoforms of GABAA̳ receptor [Beta]{208} subunit in schizophrenia and bipolar disorder

Single nucleotide polymorphisms (SNPs) in type A γ-aminobutyric acid (GABAA) receptor β2 subunit gene (GABRB2) were found to be associated with schizophrenia in Chinese, German, Japanese and Portuguese. To explore the potential functional consequences of these DNA sequence polymorphisms, this study examined the expression and electrophysiological properties of alternatively spliced products of GABRB2 along with genotypical disease-association analysis. Real-time quantitative PCR, performed with a US population of 31 schizophrenics, 30 bipolar disorders and 31 controls showed 21.7% reduction in the expression of the long isoform β2L, and 13.4% in the short isoform β2S (dominant isoform) in postmortem schizophrenic brain, but not in bipolar disorder’s brain. Furthermore, two novel short isoforms, β2S1 and β2S2, from human brain were observed and characterized. The expression of β2S2, bearing a frame-shift deletion in the terminal Exon-11, was decreased in schizophrenia (by 17.9%) and bipolar disorders (by 22.5%). The expression of the less abundant β2S1 was marginally increased in both of these mental disorders (by 43.0% in schizophrenics; by 43.7 % in bipolar disorders). Moreover, the relative expressions of β2L over β2S were significantly decreased, suggesting the occurrence of altered splicing, in schizophrenia. In male schizophrenics, the heterozygous genotypes of rs1876071 (T/C) and rs1876072 (A/G) were correlated with reduced expression of β2L and β2S, and the heterozygous of rs2546620 (A/G) and homozygous-minor of rs1876071 (C/C) and rs1876072 (G/G) were correlated with reduced expression of β2S2. In male bipolar disorders, the heterozygous genotypes of rs187269 (T/C) were correlated with reduced expression of β2S2 as well as the β2S2/β2S ratio. Electrophysiologically, the EC50 for neurotransmitter GABA was significantly reduced with β2S1, potentially compensating for the GABA deficit observed in schizophrenia. The results thus revealed genotype-dependent expression of the alternatively spliced isoforms of GABAA receptor β2 subunit, giving rise to electrophysiological consequences that could play an important role in the pathogenesis mechanism of schizophrenia