Genetic ablation of the GluK4 kainate receptor subunit causes anxiolytic and antidepressant-like behavior in mice

Abstract

There is a clear link between dysregulation of glutamatergic signaling and mood disorders. Genetic variants in the glutamate receptor gene GRIK4, which encodes the kainate receptor subunit GluK4, alter the susceptibility for depression, bipolar disorder and schizophrenia. Here we demonstrate that Grik4−/− mice have reduced anxiety and an antidepressant-like phenotype. In the elevated zero-maze, a test for anxiety and risk taking behavior, Grik4−/− mice spent significantly more time exploring the open areas of the maze. In anxiogenic tests of marble-burying and novelty-induced suppression of feeding, anxiety-like behavior was consistently reduced in knockout animals. In the forced swim test, a test of learned helplessness that is used to determine depression-like behavior, knockout mice demonstrated significantly less immobility suggesting that Grik4 ablation has an antidepressant-like effect. Finally, in the sucrose preference test, a test for anhedonia in rodents, Grik4−/− mice demonstrated increased sucrose preference. Expression of the GluK4 receptor subunit in the forebrain is restricted to the CA3 region of the hippocampus and dentate gyrus regions where KARs are known to modulate synaptic plasticity. We tested whether Grik4 ablation had effects on mossy fiber (MF) plasticity and found there to be a significant impairment in LTP likely through a loss of KAR modulation of excitability of the presynaptic MF axons. These studies demonstrate a clear anxiolytic and antidepressant phenotype associated with ablation of Grik4 and a parallel disruption in hippocampal plasticity, providing support for the importance of this receptor subunit in mood disorders.

Adolescent mice show anxiety- and aggressive-like behavior and the reduction of long-term potentiation in mossy fiber-CA3 synapses after neonatal maternal separation

“…Hipsignificant impairment in MF-CA3 LTP(Catches et al, 545 2012). Expression of the GluK4 receptor subunit is546 restricted to the CA3 region and DG regions of the hip-547 pocampus in which kainate receptors are known to mod-548 ulate synaptic plasticity(Catches et al, 2012). In the 549 present study, we found that MS induced an increased550 anxiety and decreased LTP at MF-CA3 synapse.…”

Differential gene body methylation and reduced expression of cell adhesion and neurotransmitter receptor genes in adverse maternal environment

“…Differential methylation was detected in Grin 1 , the gene for the NMDA NR1 subunit, in Grik3 and Grik4 , the genes for KA receptor subunits, in genes for glutamate receptor interacting proteins such as Grip1 , and Shank1, 2, 3 as well as in calcium ( Cacna1c ) and potassium channel ( Kcnj) genes that can all influence neuronal excitability and modulate anxiety. 58, 59, 60, 61 …”

Sex differences in animal models of schizophrenia shed light on the underlying pathophysiology

“…These included GRIK4 (kainate glutamate receptor subtype), cholinergic receptor nicotinic alpha 4 (CHRNA4) (encodes for a subtype of neuronal nicotinic acetylcholine receptor), disrupted in schizophrenia-1 (DISC-1), ErbB4, and neuregulin-1 (NRG-1). Kainate receptor, GluK4 knockout adult mice show hyperactivity and impaired pre-pulse inhibition(Lowry et al 2013), while Grik4 knockout adult mice show reduced anxiety and antidepressant behaviour(Catches et al 2012). However, both of these studies only assessed male mice, therefore no sex comparisons have been made here.…”