Loss of neuronal GSK3β reduces dendritic spine stability and attenuates excitatory synaptic transmission via β-catenin

TY - JOUR

T1 - Loss of neuronal GSK3β reduces dendritic spine stability and attenuates excitatory synaptic transmission via β-catenin

AU - Ochs, S M

AU - Dorostkar, M M

AU - Aramuni, G

AU - Schön, C

AU - Filser, S

AU - Pöschl, Julia

AU - Kremer, A

AU - Van Leuven, F

AU - Ovsepian, S V

AU - Herms, J

PY - 2015/4

Y1 - 2015/4

N2 - Central nervous glycogen synthase kinase 3β (GSK3β) 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 GSK3β either directly or indirectly. We studied how conditional knockout of GSK3β affected structural synaptic plasticity. Deletion of the GSK3β 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 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-dependent miniature excitatory postsynaptic currents. Expression of constitutively active β-catenin caused reduction in spine density and electrophysiological alterations similar to GSK3β knockout, suggesting that the effects of GSK3β knockout were mediated by the accumulation of β-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 GSK3β.

AB - Central nervous glycogen synthase kinase 3β (GSK3β) 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 GSK3β either directly or indirectly. We studied how conditional knockout of GSK3β affected structural synaptic plasticity. Deletion of the GSK3β 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 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-dependent miniature excitatory postsynaptic currents. Expression of constitutively active β-catenin caused reduction in spine density and electrophysiological alterations similar to GSK3β knockout, suggesting that the effects of GSK3β knockout were mediated by the accumulation of β-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 GSK3β.

KW - Animals

KW - Antineoplastic Agents, Hormonal

KW - Bacterial Proteins

KW - Cerebral Cortex

KW - Dendritic Spines

KW - Excitatory Amino Acid Agents

KW - Excitatory Postsynaptic Potentials

KW - GABA Antagonists

KW - Gene Expression Regulation

KW - Glycogen Synthase Kinase 3

KW - Hippocampus

KW - In Vitro Techniques

KW - Luminescent Proteins

KW - Mice

KW - Mice, Transgenic

KW - Neurons

KW - Patch-Clamp Techniques

KW - Picrotoxin

KW - Tamoxifen

KW - beta Catenin

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/mp.2014.55

DO - 10.1038/mp.2014.55

M3 - SCORING: Journal article

C2 - 24912492

VL - 20

SP - 482

EP - 489

JO - MOL PSYCHIATR

JF - MOL PSYCHIATR

SN - 1359-4184

IS - 4

ER -