Novel α7 nicotinic receptor isoforms and deficient cholinergic transcription in schizophrenia

Abnormal alpha 7 nicotinic acetylcholine receptor activity contributes to sensory gating and cognitive deficits in schizophrenic individuals. Negligible differences in alpha 7 mRNA levels between disease and control states have led to conclusions that cholinergic dysfunction in schizophrenia (SZ) must occur post-transcriptionally. Alternatively, we propose that the dysregulation of splice variants of the alpha 7 receptor could account for cholinergic deficiencies observed in this disease. Here, we isolated multiple alpha 7 splice variants including exon deletions and those associated with a novel 124-127 base insertion following exon 4. Transcripts containing this new exon originated from sense strand-oriented RNA (vs. antisense), and in silico translations produced putative subunits with unique amino termini. Quantitative real-time polymerase chain reaction analyses indicated that one novel isoform was significantly downregulated (P <= 0.03) in post-mortem prefrontal cortex of individuals with SZ (n = 35) compared with controls (n = 34). Ten brain regions (cerebellum, thalamus, corpus callosum, caudate, putamen and five areas of the cortex) were further screened for alpha 7 isoforms in three individuals of each group. Semiquantitative analyses showed that each alpha 7 mRNA subtype was present in each brain region, but all were particularly deficient in the corpus callosum in schizophrenics vs. controls (P <= 0.0002 to 0.05 for different isoforms). Our data demonstrate that alpha 7 transcription is altered in several ways in SZ, suggesting that transcription-level mechanisms could account in part for the impaired cholinergic neurotransmission observed in this disease.