Role of Neuronal TRPC6 Channels in Synapse Development, Memory Formation and Animal Behavior

Abstract

The transient receptor potential cation channel, subfamily C, member 6 (TRPC6), has been believed to adjust the formation of an excitatory synapse. The positive regulation of TRPC6 engenders synapse enlargement and improved learning and memory in animal models. TRPC6 is involved in different synaptoprotective signaling pathways, including antagonism of N-methyl-D-aspartate receptor (NMDAR), activation of brain-derived neurotrophic factor (BDNF) and postsynaptic store-operated calcium entry. Positive regulation of TRPC6 channels has been repeatedly shown to be good for memory formation and storage. TRPC6 is mainly expressed in the hippocampus, particularly in the dentate granule cells, cornu Ammonis 3 (CA3) pyramidal cells and gamma-aminobutyric acid (GABA)ergic interneurons. It has been observed that TRPC6 agonists have a great influence on animal behavior including memory formation and storage The purpose of this review is to collect the available information on the role of TRPC6 in memory formation in various parts of the brain to understand how TRPC6-specific pharmaceutical agents will affect memory in distinct parts of the central nervous system (CNS).

Keywords: TRPC6; behavior; memory; neuroprotection.

Figure 1

Neuroprotective intracellular signaling pathways in the central nervous system involving TRPC6 activation. A detailed description of pathways is given in the 3rd, 4th and 5th sections. Presumably, TRPC6 may impede the extrasynaptic NR2B-containing NMDAR-dependent calcium influx via calcineurin-involving dephosphorylation mechanism (see the dashed lines). On the other hand, activation of synaptic NR2A-containing NMDAR may increase TRPC6 mRNA synthesis through a calcineurin/nuclear factor of activated T-cells-dependent pathway in cortical neurons (see the solid lines). Agonism of synaptic NMDAR has been proposed to underlie the activation of synaptoprotective store-operated calcium entry via TRPC6 in hippocampal silent synapses. TPRC6 is key component of store-operated calcium entry in hippocampal neurons. TRPC6 may be activated directly either by DAG or pharmacological agent such as hyperforin as well as by store-depletion (following IP3R activation). Upon store depletion of ER, the STIM2 detects calcium level reduction and activates Orai2/TRPC6 channels complex. Calcium entry via TRPC6-neuronal SOCE is needed to activate CaMKII, which can phosphorylate AMPAR. This promotes AMPARs trafficking to the post-synaptic membrane, which increases membrane depolarization and enhances NMDAR’s contribution to LTP maintenance. In addition, in neuronal tumor cells TRPC6-induced calcium entry is essential for the biosynthesis of endocannabinoids (2-AG, AEA) that have anti-inflammatory properties. Supposedly, neuroprotective effects are achieved by suppressing NF-κB via activation of the PPARγ. The binding of BDNF to TrkB results in the PLC-dependent activation of TRPC6. Calcium influx through TRPC6 may also activate CREB through three signal cascades: Ras/MEK/ERK, RAS/PI3K/Akt, and CaM/CAMKIV. Neuroprotective effect is achieved via CREB-dependent activation of the BDNF transcription. Moreover, in DGC and GABAergic interneurons TRPC6 may impact on Kv4.3 translocation to the neuronal membrane via ERK-dependent signaling (indicated by a wavy line). Kv4.3 impedes fast-spiking in interneurons, and afterwards increases neuronal excitability in principal neurons. Thus, TRPC6 possibly plays a role in regulation of neuronal excitability. Finally, TRPC6-ERK1/2 neuroprotective signaling pathway has been also reported to protect DGC via facilitation of mitochondrial fission (indicated by a wavy line).