Capsaicin-Induced Impairment of Functional Network Dynamics in Mouse Hippocampus via a TrpV1 Receptor-Independent Pathway: Putative Involvement of Na(+)/K(+)-ATPase

The vanilloid compound capsaicin (Cp) is best known to bind to and activate the transient receptor potential vanilloid receptor-1 (TrpV1). A growing number of studies use capsaicin as a tool to study the role of TrpV1 in the central nervous system (CNS). Although most of capsaicin’s CNS effects have been reported to be mediated by TrpV1 activation, evidence exists that capsaicin can also trigger functional changes in hippocampal activity independently of TrpV1. Recently, we have reported that capsaicin induces impairment in hippocampal gamma oscillations via a TrpV1-independent pathway. Here, we dissect the underlying mechanisms of capsaicin-induced alterations to functional network dynamics. We found that capsaicin induces a reduction in action potential (AP) firing rate and a subsequent loss of synchronicity in pyramidal cell (PC) spiking activity in hippocampus. Moreover, capsaicin induces alterations in PC spike-timing since increased first-spike latency was observed after capsaicin treatment. First-spike latency can be regulated by the voltage-dependent potassium current D (I(D)) or Na(+)/K(+)-ATPase. Selective inhibition of I(D) via low 4-AP concentration and Na(+)/K(+)-ATPase using its blocker ouabain, we found that capsaicin effects on AP spike timing were completely inhibited by ouabain but not with 4-AP. In conclusion, our study shows that capsaicin in a TrpV1-independent manner and possibly involving Na(+)/K(+)-ATPase activity can impair cognition-relevant functional network dynamics such as gamma oscillations and provides important data regarding the use of capsaicin as a tool to study TrpV1 function in the CNS. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12035-019-01779-3) contains supplementary material, which is available to authorized users.