Novel alpha7 nicotinic receptor isoforms and deficient cholinergic transcription in schizophrenia.
Abnormal alpha7 nicotinic acetylcholine receptor activity contributes to sensory gating and cognitive deficits in schizophrenic individuals. Negligible differences in alpha7 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 alpha7 receptor could account for cholinergic deficiencies observed in this disease. Here, we isolated multiple alpha7 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 < or = 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 alpha7 isoforms in three individuals of each group. Semiquantitative analyses showed that each alpha7 mRNA subtype was present in each brain region, but all were particularly deficient in the corpus callosum in schizophrenics vs. controls (P < or = 0.0002 to 0.05 for different isoforms). Our data demonstrate that alpha7 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.
Severance
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Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, 600 N Wolfe Street, Blalock 1105, Baltimore, MD21287-4933, USA. eseverance@jhmi.edu
Yolken
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D000328:Adult; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D001931:Brain Mapping; D002872:Chromosome Deletion; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics; D012326:RNA Splicing; D011978:Receptors, Nicotinic / Q000235:genetics*; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D012565:Schizophrenic Psychology; D009435:Synaptic Transmission / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics*; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579167:Chrna7 protein, human; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor