Abstract
Transient Receptor Potential Canonical 6 (TRPC6) has been suggested to be involved in synapse function and contribute to hippocampal-dependent cognitive processes. Gene silencing of TRPC6 was performed by injecting adeno-associated virus (AAV) expressing TRPC6-specific shRNA (shRNA-TRPC6) into the hippocampal dentate gyrus (DG). Spatial learning, working memory and social recognition memory were impaired in the shRNA-TRPC6 treated mice compared to control mice after 4 weeks. In addition, gene ontology (GO) analysis of RNA-sequencing revealed that viral intervention of TRPC6 expression in DG resulted in the enrichment of the process of synaptic transmission and cellular compartment of synaptic structure. KEGG analysis showed PI3K-Akt signaling pathway were significantly down-regulated. Furthermore, the shRNA-TRPC6 treatment reduced dendritic spines of DG granule neurons, in terms of spine loss, the thin and mushroom types predominated. Accompanying the spine loss, the levels of PSD95, pAkt and CREB in the hippocampus were decreased in the shRNA-TRPC6 treated animals. Taken together, our results suggest that knocking down TRPC6 in the DG have a disadvantageous effect on cognitive processes.
Highlights
The transient receptor potential channels (TRPCs) comprised of seven different channels (TRPC1TRPC7), are calcium-permeable, non-selective cation channels containing six transmembrane structural domains (Dietrich et al, 2005; Nakata and Nakamura, 2007; Venkatachalam and Montell, 2007)
The Transient Receptor Potential Canonical 6 (TRPC6) mainly localizes in the dentate gyrus (DG) (Kim et al, 2013; Nagy et al, 2013), we infused the shRNATRPC6 into the DG mediating TRPC6 knockdown
The expression of TRPC6 in the DG area was remarkably reduced after short hairpin RNA (shRNA)-TRPC6 virus transduction when compared to the control vector (Figure 2A)
Summary
The transient receptor potential channels (TRPCs) comprised of seven different channels (TRPC1TRPC7), are calcium-permeable, non-selective cation channels containing six transmembrane structural domains (Dietrich et al, 2005; Nakata and Nakamura, 2007; Venkatachalam and Montell, 2007). TRPCs, the TRPC6 channel is emerging as a prominent target for the control of synapse formation involved in the cognitive function (Zhou et al, 2008). The hippocampus is involved in learning, memory formation, spatial coding, and mood regulation (Douglas, 1967; Eichenbaum, 2017). Synapse and dendrite abnormalities occurred in DG granule cells (DGCs) are associated with altered learning and memory in both humans and mice. Previous studies have shown that TRPC6 is expressed in pyramidal neurons, DGCs, interneurons and some glial cells in the hippocampus (Chung et al, 2006; Tai et al, 2008). It has been confirmed that TRPC6 is critical for excitatory synapse formation, which is further supported by the finding that TRPC6 overexpression could increase dendritic spine density (Zhou et al, 2008)
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