Selective deletion of forebrain glycogen synthase kinase 3ß reveals a central role in serotonin-sensitive anxiety and social behaviour.

ABSTRACT

Serotonin (5-HT) neurotransmission is thought to underlie mental illnesses, such as bipolar disorder, depression, autism and schizophrenia. Independent studies have indicated that 5-HT or drugs acting on 5-HT neurotransmission regulate the serine/threonine kinase glycogen synthase kinase 3ß (GSK3ß). Furthermore, GSK3ß inhibition rescues behavioural abnormalities in 5-HT-deficient mice with a loss-of-function mutation equivalent to the human variant (R441H) of tryptophan hydroxylase 2. In an effort to define neuroanatomical correlates of GSK3ß activity in the regulation of behaviour, we generated CamKIIcre-floxGSK3ß mice in which the gsk3b gene is postnatally inactivated in forebrain pyramidal neurons. Behavioural characterization showed that suppression of GSK3ß in these brain areas has anxiolytic and pro-social effects. However, while a global reduction of GSK2ß expression reduced responsiveness to amphetamine and increased resilience to social defeat, these behavioural effects were not found in CamKIIcre-floxGSK3ß mice. These findings demonstrate a dissociation of behavioural effects related to GSK3 inhibition, with forebrain GSK3ß being involved in the regulation of anxiety and sociability while social preference, resilience and responsiveness to psychostimulants would involve a function of this kinase in subcortical areas such as the hippocampus and striatum.