THE ROLE OF A HUMAN POLYMORPHISM IN THE Α5 NICOTINIC ACETYLCHOLINE RECEPTOR IN CORTICAL INHIBITORY CIRCUITS DURING COGNITIVE BEHAVIOR

Studies have pinpointed single-nucleotide polymorphisms (SNPs) that predispose individuals to schizophrenia. One such SNP, rs16969968 (α5SNP), in the α5 nicotinic acetylcholine receptor (nAChR) subunit, results in a loss of function. This SNP is present in approximately 37% of Europeans and 50% of Middle Eastern individuals and has been linked to nicotine addiction. In the prefrontal cortex (PFC), the α5 nAChR is expressed in vasoactive intestinal peptide (VIP)-positive interneurons in cortical layers 2/3 and pyramidal neurons in cortical layer 6. In α5SNP mice, reduced VIP interneuron activity increases somatostatin-mediated inhibition of layer 2/3 pyramidal neurons. However, the impact of the α5SNP on cognitive behavior remains poorly understood. To investigate the role of the α5SNP in cognition, we performed behavioral tests, including the Attentional Set-Shifting Task (ASST) and the three-chamber social interaction test. The ASST assesses PFC-dependent cognitive flexibility and is analogous to the Wisconsin Card Sorting Test in humans. While α5SNP mice exhibited normal learning performance, they showed impairments in rule reversal and rule shifting, indicating a deficit in cognitive flexibility. They also displayed deficits in social behavior. These impairments were rescued by administration of nicotinic receptor agonists. Inhibition of VIP interneurons produced deficits similar to those observed in α5SNP mice. Using two-photon calcium imaging in head-fixed mice and miniscope calcium imaging of VIP interneurons and pyramidal neurons in freely behaving mice during task performance, we aim to unravel underlying mechanisms. Together, these results demonstrate that the α5SNP disrupts cognitive flexibility and sociability and provide novel therapeutic strategies for drug development.