In α5-SNP-expressing and α5-knockout mice, lower activity of vasoactive intestinal polypeptide (VIP) interneurons resulted in an increased somatostatin (SOM) interneuron inhibitory drive over layer II/III pyramidal neurons. Two-photon calcium imaging in awake mouse models showed that nicotine can differentially influence PFC pyramidal cell activity by nAChR modulation of layer II/III hierarchical inhibitory circuits. Here we show that mice expressing a human α5SNP exhibit neurocognitive behavioral deficits in social interaction and sensorimotor gating tasks.

Mice with altered nAChR gene function exhibit PFC-dependent behavioral deficits 9– 11, but it is unknown how the corresponding human polymorphisms alter the cellular and circuit mechanisms underlying behavior. Recently, genome-wide association studies (GWAS) identified single-nucleotide polymorphisms (SNPs) in the human CHRNA5 gene, encoding the α5 nAChR subunit, that increase the risks for both smoking and schizophrenia 7, 8. PFC spontaneous default activity 3 is altered in neuropsychiatric disorders 4, including schizophrenia 5-a disorder that can be accompanied by heavy smoking 6. The prefrontal cortex (PFC) underlies higher cognitive processes 1 that are modulated by nicotinic acetylcholine receptor (nAChR) activation by cholinergic inputs 2.

Vector vs raster ppu