Abstract
Genetic variations and adverse environmental events
in utero
or shortly after birth can lead to abnormal brain development and increased risk of schizophrenia. γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian brain, plays a vital role in normal brain development. GABA synthesis is controlled by enzymes derived from two glutamic acid decarboxylase (GAD) genes,
GAD1
and
GAD2
, both of which produce transcript isoforms. While the full-length
GAD1
transcript (GAD67) has been implicated in the neuropathology of schizophrenia, the transcript structure of
GAD1
in the human brain has not been fully characterized. In this study, with the use of RNA sequencing and PCR technologies, we report the discovery of 10 novel transcripts of
GAD1
in the human brain. Expression levels of four novel
GAD1
transcripts (8A, 8B, I80, and I86) showed a life span trajectory expression pattern that is anticorrelated with the expression of the full-length
GAD1
transcript. In addition, methylation levels of two CpG loci within the putative
GAD1
promoter were significantly associated with the schizophrenia-risk SNP rs3749034 and with the expression of GAD25 in DLPFC. Moreover, schizophrenia patients who had completed suicide and/or were positive for nicotine exposure had significantly higher full-length
GAD1
expression in the DLPFC. Alternative splicing of
GAD1
and epigenetic state appear to play roles in the developmental profile of GAD1 expression and may contribute to GABA dysfunction in the PFC and hippocampus of patients with schizophrenia.