TRPM2, a Susceptibility Gene for Bipolar Disorder, Regulates Glycogen Synthase Kinase-3 Activity in the Brain

Abstract

Bipolar disorder (BD) is a psychiatric disease that causes mood swings between manic and depressed states. Although genetic linkage studies have shown an association between BD and TRPM2, a Ca 2ϩ -permeable cation channel, the nature of this association is unknown. Here, we show that D543E, a mutation of Trpm2 that is frequently found in BD patients, induces loss of function. Trpm2-deficient mice exhibited BD-related behavior such as increased anxiety and decreased social responses, along with disrupted EEG functional connectivity. Moreover, the administration of amphetamine in wild-type mice evoked a notable increase in open-field activity that was reversed by the administration of lithium. However, the anti-manic action of lithium was not observed in the Trpm2 Ϫ / Ϫ mice. The brains of Trpm2 Ϫ / Ϫ mice showed a marked increase in phosphorylated glycogen synthase kinase-3 (GSK-3), a key element in BD-like behavior and a target of lithium. In contrast, activation of TRPM2 induced the dephosphorylation of GSK-3 via calcineurin, a Ca 2ϩ -dependent phosphatase. Importantly, the overexpression of the D543E mutant failed to induce the dephosphorylation of GSK-3. Therefore, we conclude that the genetic dysfunction of Trpm2 causes uncontrolled phosphorylation of GSK-3, which may lead to the pathology of BD. Our findings explain the long-sought etiologic mechanism underlying the genetic link between Trpm2 mutation and BD.

The Transient Receptor Potential Melastatin 2 (TRPM2) Channel Contributes to β-Amyloid Oligomer-Related Neurotoxicity and Memory Impairment

“…The importance of TRPM2 to CNS function is underscored by studies implicating TRPM2 in diseases, including stroke/ischemia (Jia et al, 2011;Verma et al, 2012;Alim et al, 2013), neurodegenerative diseases (Fonfria et al, 2005;Hermosura et al, 2008), bipolar disorder (Xu et al, 2006;Jang et al, 2015), and epilepsy (Katano et al, 2012). These studies suggest that abnormal TRPM2 activity can profoundly influence CNS function and pathology.…”

“…For example, genetic ablation of TRPM2 is associated with increased phosphorylation of Akt and inactivation of glycogen synthase kinase GSK3␤ Jang et al, 2015), which was recently found to be beneficial in AD mouse models (Kazim et al, 2014). This effect could balance GSK3␤ activation by PP2B, a phosphatase whose activity has been directly linked to NMDAR dysregulation by A␤ (Sny- der et al, 2005).…”

Sequencing of sporadic Attention‐Deficit Hyperactivity Disorder (ADHD) identifies novel and potentially pathogenic de novo variants and excludes overlap with genes associated with autism spectrum disorder

“…The 6 validated missense SNVs are each exceedingly rare (maximum allele frequency of 4.24×10 −5 ), highly conserved, offering several additional possible candidates of study in the pathogenesis of sporadic ADHD. Notably, CSMD2 and TRPM2 , both of which were identified in the same sporadic ADHD proband in Family 10, each have been reported in association with other psychiatric disorders; adult ADHD (Lesch et al, 2008) and schizophrenia (Håvik et al, 2011) for CSMD2 , and bipolar disorder for TRPM2 (McQuillin et al, 2005; Jang et al, 2015). Two additional de novo mutations identified in ADHD probands (see Supplemental Table 3) were found to have been transmitted to the probands in other families.…”

“… g TRPM2 common variants have previously been associated with bipolar disorder (McQuillin et al, 2005; Jang et al, 2015). …”

Three Potential Risk Genes for Bipolar Disorder: MT1E, MT1X and CX3CR1

“…For example, BDNF, RELN and ANK3 were suggested as potential biomarkers for the disease [5][6][7] . Jang et al found that the genetic dysfunction of Trpm2 causes uncontrolled phosphorylation of GSK-3, which may lead to the pathology of BP [8] .…”