Nicotinic modulation of hierarchal inhibitory control over prefrontal cortex resting state dynamics: modeling of genetic modification and schizophrenia-related pathology

Nicotinic acetylcholine receptors (nAChRs) strongly modulate the cholinergic drive to a hierarchy of inhibitory neurons in the superficial layers of the PFC, critical to cognitive processes. Genetic deletion of various types of nAChRs, located on specific interneurons, impacts the properties of ultra-slow transitions between high and low activity states (H-states and L-states, respectively), recorded in mice during quiet wakefulness. In addition, recent data indicate that a genetic mutation of the 5 nAChR subunit located on vasoactive intestinal polypeptide (VIP) inhibitory neurons, the rs16969968 single nucleotide polymorphism (5 SNP), appears to be responsible for \"hypofrontality\" observed in schizophrenia. Chronic nicotine application to 5 SNP mice restores neural activity to control levels. Using firing rate models of hierarchically organized neural populations, we showed that the change of activity patterns recorded in the genetically modified mice can be explained by a change of activity state stability, differentially modulated by cholinergic inputs to parvalbumin (PV), somatostatin (SOM) or VIP inhibitory populations. A change in amplitude, but not duration of H-states fully account for the lowered pyramidal (PYR) firing rates recorded in 5 SNP mice. We demonstrate that desensitization and upregulation of {beta}2 nAChRs located on SOM interneurons, but not activation of 5 nAChRs located on VIP interneurons, by chronic nicotine application could account for activity normalization recorded in 5 SNP mice. The model implies that subsequent nicotine withdrawal should lead to PYR activity depression more severe than the original hypofrontality caused by SNP mutation.