Decreased Anxiety-Like Behavior and G_αq/11-Dependent Responses in the Amygdala of Mice Lacking TRPC4 Channels

Abstract

Transient receptor potential (TRP) channels are abundant in the brain where they regulate transmission of sensory signals. The expression patterns of different TRPC subunits (TRPC1, 4, and 5) are consistent with their potential role in fear-related behaviors. Accordingly, we found recently that mutant mice lacking a specific TRP channel subunit, TRPC5, exhibited decreased innate fear responses. Both TRPC5 and another member of the same subfamily, TRPC4, form heteromeric complexes with the TRPC1 subunit (TRPC1/5 and TRPC1/4, respectively). As TRP channels with specific subunit compositions may have different functional properties, we hypothesized that fear-related behaviors could be differentially controlled by TRPCs with distinct subunit arrangements. In this study, we focused on the analysis of mutant mice lacking the TRPC4 subunit, which, as we confirmed in experiments on control mice, is expressed in brain areas implicated in the control of fear and anxiety. In behavioral experiments, we found that constitutive ablation of TRPC4 was associated with diminished anxiety levels (innate fear). Furthermore, knockdown of TRPC4 protein in the lateral amygdala via lentiviralmediated gene delivery of RNAi mimicked the behavioral phenotype of constitutive TRPC4-null (TRPC4 ؊/؊ ) mouse. Recordings in brain slices demonstrated that these behavioral modifications could stem from the lack of TRPC4 potentiation in neurons in the lateral nucleus of the amygdala through two G ␣q/11 protein-coupled signaling pathways, activated via Group I metabotropic glutamate receptors and cholecystokinin 2 receptors, respectively. Thus, TRPC4 and the structurally and functionally related subunit, TRPC5, may both contribute to the mechanisms underlying regulation of innate fear responses.

Selectivity and Evolutionary Divergence of Metabotropic Glutamate Receptors for Endogenous Ligands and G Proteins Coupled to Phospholipase C or TRP Channels

“…These data indicate that the dominant negative G␣ o completely suppresses G i/o signaling by mGluR1, but has little or no effect on G␣ q/11 activation by either mGluR1 or the M3 muscarinic receptor. Recent evidence from behavioral and brain slice experiments in wild type and TRPC4-knock-out mice suggests a physiologically important role for mGluR1 activation of TRPC4; however, in this work it was assumed that mGluR1 regulates TRPC4 channels exclusively through G␣ q/11 stimulation of PLC (47). Both the inhibitory effects of PTX and dominant negative G␣ subunits on mGluR1 activation of TRPC4␤ The remainder of the C-terminal domain is highly divergent.…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Another recently discovered TRP channel involved in anxiety is TRPC4 (Riccio et al, 2014). Of note, Trpc4 KO mice also show reduced cocaine self-administration (Rasmus et al, 2013), implying a role for addictive behavior.…”

Dynamic NHERF interaction with TRPC4/5 proteins is required for channel gating by diacylglycerol

“…They are widely expressed in many tissues, including brain, kidney, and the vascular system. High expression levels are found in the central nervous system where TRPC4 and -5 are involved in amygdala function and fear-related behavior (1,2), seizure, and excitotoxicity (3). Furthermore, TRPC5 channels are implicated in neuronal depolarization and bursting during epiletiform seizures (4) and regulate hippocampal neurite length and growth cone morphology (5).…”

“…DAG-mediated TRPC5 channel inhibition was shown to be PKC dependent (10). Furthermore, TRPC4 and -5 channels can be activated by depleting PIP 2 (11,12), contrary to TRPC6 and -7 channels, which are inhibited by PIP 2 depletion (13). However, there are first hints to show that endogenously expressed TRPC5 channels might be DAG sensitive (14) but mechanistic insight is lacking so far.…”