TRPC3 channels critically regulate hippocampal excitability and contextual fear memory

Abstract

Memory formation requires de novo protein synthesis, and memory disorders may result from misregulated synthesis of critical proteins that remain largely unidentified. Plasma membrane ion channels and receptors are likely candidates given their role in regulating neuron excitability, a candidate memory mechanism. Here we conduct targeted molecular monitoring and quantitation of hippocampal plasma membrane proteins from mice with intact or impaired contextual fear memory to identify putative candidates. Here we report contextual fear memory deficits correspond to increased Trpc3 gene and protein expression, and demonstrate TRPC3 regulates hippocampal neuron excitability associated with memory function. These data provide a mechanistic explanation for enhanced contextual fear memory reported herein following knockdown of TRPC3 in hippocampus. Collectively, TRPC3 modulates memory and may be a feasible target to enhance memory and treat memory disorders.

Systems genetics identifies modifiers of Alzheimer’s disease risk and resilience

“…Calcium regulation has also been shown to directly modulate Aβ production, thereby providing a mechanistic link between Trpc3 channels and Aβ42 modulation (LaFerla, 2002). In addition, our lab has previously implicated Trpc3 as causally involved in the regulation of neuronal excitability and cognitive function, providing a biological link between Trpc3 channels and cognitive symptoms of AD (Neuner et al, 2015). It was our hypothesis that targeting a gene that is both a known cognitive enhancer and putative mediator of Aβ42 levels would likely provide a double benefit to AD carriers by better allowing neurons to participate in networks critical for learning.…”

“…Misregulation of calcium signaling has previously been implicated in the pathogenesis of AD (LaFerla, 2002), and Trpc3 itself has recently been implicated in neuronal excitability and cognitive function in adult mice (Neuner et al, 2015). In addition, Trpc3 function has been shown to be sensitive to cellular cholesterol (Graziani et al, 2006), a pathway closely linked to AD by GWAS hits such as APOE, CLU, and ABCA7 (Karch and Goate, 2015).…”

“…Since TRPC3 protein is increased in hippocampus from 5XFAD mice compared to Ntg controls [ Figure 6A, n = 4/grp, t(1,6) = 3.7, p = 0.01], we injected our previously validated AAV9 viral vector containing either shRNA targeting Trpc3 (shRNA-Trpc3) or a scrambled shRNA control (shRNA-Ctrl) (Neuner et al, 2015) directly in the dorsal hippocampus of presymptomatic male 4 month-old 5XFAD-B6SJL mice (Oakley et al, 2006). This strain was chosen as it a susceptible strain with robust amyloid deposition when compared to mice from our AD-BXD panel ( Figure 5A).…”

“…We next assessed the impact of the AD transgene in our panel on long-term contextual fear memory (CFM) as described previously (Neuner et al, 2015). AD-BXD mice exhibited impaired CFM by 14 months (Figure 1E), and the extent of variation in CFM at both age points varied significantly by strain [n = 355 mice (212 female/143 male) across 28 strains and 2 ages -effect of strain, F(27,354) = 3.6, p < 0.001, Figure 4A-B; no main effect of sex (p = 0.4)].…”

“…http://dx.doi.org/10.1101/225714 doi: bioRxiv preprint first posted online Nov. 27, 2017; Contextual fear conditioning Following 3 days of habituation to transport and to the testing room, mice were trained on a standard contextual fear conditioning paradigm as previously described (Neuner et al, 2015). Training consisted of a 180s baseline period followed by four mild foot shocks (1s, 0.9mA), separated by 115 ± 20s.…”