Loss of neuronal GSK3? reduces dendritic spine stability and attenuates excitatory synaptic transmission via ?-catenin.

ABSTRACT: Central nervous glycogen synthase kinase 3? (GSK3?) is implicated in a number of neuropsychiatric diseases, such as bipolar disorder, depression, schizophrenia, fragile X syndrome or anxiety disorder. Many drugs employed to treat these conditions inhibit GSK3? either directly or indirectly. We studied how conditional knockout of GSK3? affected structural synaptic plasticity. Deletion of the GSK3? gene in a subset of cortical and hippocampal neurons in adult mice led to reduced spine density. In vivo imaging revealed that this was caused by a loss of persistent spines, whereas stabilization of newly formed spines was reduced. In electrophysiological recordings, these structural alterations correlated with a considerable drop in the frequency and amplitude of ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-dependent miniature excitatory postsynaptic currents. Expression of constitutively active ?-catenin caused reduction in spine density and electrophysiological alterations similar to GSK3? knockout, suggesting that the effects of GSK3? knockout were mediated by the accumulation of ?-catenin. In summary, changes of dendritic spines, both in quantity and in morphology, are correlates of experience-dependent synaptic plasticity; thus, these results may help explain the mechanism of action of psychotropic drugs inhibiting GSK3?.

SUBMITTER: Ochs SM 

PROVIDER: S-EPMC4378257 | biostudies-other | 2015 Apr

REPOSITORIES: biostudies-other