Kainate receptors (KARs) represent a class of glutamate receptors (GluRs) that respond to glutamate and gamma-amino-butyric acid (GABA) and regulate synaptic plasticity in brain regions involved in mood regulation, including the anterior cingulate cortex, hippocampus, and amygdala. The KAR family includes five subunits: GluR 5-7 and KA 1-2 (also called glutamate receptor ionotropic kainate (GRIK) 1-5 respectively). The receptors comprise trimeric proteins that form the receptor channel. GluRs 5 and 6 can undergo RNA editing, resulting in altered channel permeability to different ions. The human GluR6 gene is located on chromosome 6q16.3-q21, a region of which has been implied in several bipolar disorder linkage studies. Recent genetic association studies directly implicate GluR6 as a contributing factor to increased risk of mood disorders. However, the roles of kainate receptors in mood regulation are largely unknown. Therefore we conducted studies in GluR5 and GluR6 knockout (KO) and wildtype (WT) control mice using a behavioral test battery for mood disorders and neurochemical experiments.
GluR5 and 6 KO mice appeared to attain normal growth, and lacked neurological abnormalities. Compared to WT and GluR5 KO mice, GluR6 KO mice consumed more saccharin-sweetened solution in this test of hedonic activity. GluR6 KO mice traveled longer distances, entered and spent more time in the center of the open field, which serves as an index for explorative risk-taking activities. The hyperactivity of GluR6 KO persisted throughout the entire experimental period, and the mice showed no habituation to the open-field arena. GluR6 KO mice exhibited aggressiveness in both the social interaction and resident-intruder tests. GluR6 KO had more activity in the open-arm of an elevated-plus maze and less immobility in the forced-swim test. GluR6 KO mice also exhibited higher responses in amphetamine challenge test. Thus, GluR6, but not GluR5, KO mice display behavioral excitement, greater aggressiveness, and hyperhedonia;these traits appear to phenocopy the clinical manic state. Furthermore, chronic lithium treatment relieved key behavioral alterations of GluR6 KO mice by reducing the levels of heightened locomotor activity, aggravated aggression, and supersensitivity to amphetamine. Neurochemical studies did not reveal any significant alterations in levels of the glutamate receptor subtypes called AMPA and NMDA;however, hippocampal and prefrontal cortical membrane levels of GluR5 and KA-2 receptors were decreased in GluR6 KO mice, and chronic lithium treatment did not affect these decreases. Taken together, the data strongly support the notion that GluR6-mediated neurotransmission is a critical modulator of mood related behavior and that genetic dysfunction of GluR6 can result in behavioral display of mania-like behavior. Future studies are needed to elucidate the effects of human GluR6 single nucleotide polymorphisms (SNPs) on GluR6-related neurotransmission, brain regions involved in GluR6-mdiated behavioral plasticity, and GluR6 as a novel therapeutic target for controlling mood state disorders.
Concerns that antidepressants (SSRIs) are potentially associated with suicidal thinking and/or behavior, especially in children and adolescents, led the FDA to issue a black-box warning for those medications. The warning has resulted in decreased SSRI prescriptions in the young, with a concomitant increase in suicide rates in this population, emphasizing the need to identify the mechanisms whereby SSRIs may be associated with suicidal ideation. Recent genetic studies show that the gene GRIK2 (which encodes for the GluR6 glutamate receptor) confers sensitivity to treatment-emergent suicidal ideation in individuals with mood disorders. Additionally, the GRIK2 gene has been suggested to represent a bipolar susceptibility gene. Notably, antidepressants may be deleterious to bipolar disorder patients, because they may induce cycle acceleration or cause agitation/dysphoria. Considering these and our findings with GluR6 KO mice, we hypothesized that mice (especially prepubertal mice) with altered GluR6 function would exhibit elevated levels of these behaviors as a response to SSRIs. Our data show that aggression levels increased with age in both WT and GluR6 KO groups. Citalopram treatment for two weeks increased aggression in the prepubertal GluR6 KO mice, but not in the prepubertal WT mice. Current studies are aimed at confirming and extending the preliminary findings.
| Malkesman, Oz; Austin, Daniel R; Chen, Guang et al. (2009) Reverse translational strategies for developing animal models of bipolar disorder. Dis Model Mech 2:238-45 |
| Malkesman, Oz; Pine, Daniel S; Tragon, Tyson et al. (2009) Animal models of suicide-trait-related behaviors. Trends Pharmacol Sci 30:165-73 |
