PT  - JOURNAL ARTICLE
AU  - Marie Rooy
AU  - Fani Koukouli
AU  - Uwe Maskos
AU  - Boris Gutkin
TI  - Nicotinic modulation of hierarchal inhibitory control over prefrontal cortex resting state dynamics: modeling of genetic modification and schizophreniarelated pathology
AID  - 10.1101/301051
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 301051
4099  - http://biorxiv.org/content/early/2018/04/13/301051.short
4100  - http://biorxiv.org/content/early/2018/04/13/301051.full
AB  - 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 α5 nAChR subunit located on vasoactive intestinal polypeptide (VIP) inhibitory neurons, the rs16969968 single nucleotide polymorphism (α5 SNP), appears to be responsible for “hypofrontality” observed in schizophrenia. Chronic nicotine application to α5 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 α5 SNP mice. We demonstrate that desensitization and upregulation of β2 nAChRs located on SOM interneurons, but not activation of α5 nAChRs located on VIP interneurons, by chronic nicotine application could account for activity normalization recorded in α5 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.