TRPV1 regulates excitatory innervation of OLM neurons in the hippocampus

Joaquin I Hurtado-Zavala,Julie M Miwa,Henry A Lester,Andre Fischer,Markus A Stahlberg,Saheeb Ahmed,Ankit Awasthi,Camin Dean,Christiane Bolleyer,Kristin Anderson,Binu Ramachandran,Rashi Halder,Jochen F Staiger,Robin J Wagener,Ryan M Drenan

doi:10.1038/ncomms15878

Abstract

TRPV1 is an ion channel activated by heat and pungent agents including capsaicin, and has been extensively studied in nociception of sensory neurons. However, the location and function of TRPV1 in the hippocampus is debated. We found that TRPV1 is expressed in oriens-lacunosum-moleculare (OLM) interneurons in the hippocampus, and promotes excitatory innervation. TRPV1 knockout mice have reduced glutamatergic innervation of OLM neurons. When activated by capsaicin, TRPV1 recruits more glutamatergic, but not GABAergic, terminals to OLM neurons in vitro. When TRPV1 is blocked, glutamatergic input to OLM neurons is dramatically reduced. Heterologous expression of TRPV1 also increases excitatory innervation. Moreover, TRPV1 knockouts have reduced Schaffer collateral LTP, which is rescued by activating OLM neurons with nicotine—via α2β2-containing nicotinic receptors—to bypass innervation defects. Our results reveal a synaptogenic function of TRPV1 in a specific interneuron population in the hippocampus, where it is important for gating hippocampal plasticity.

Highlights

transient receptor potential vanilloid 1 (TRPV1) is an ion channel activated by heat and pungent agents including capsaicin, and has been extensively studied in nociception of sensory neurons
We further found that the reduced Schaffer collateral long-term potentiation (LTP) observed in hippocampal slices from TRPV1 knockouts is caused by the decrease in excitatory innervation of OLM cells: LTP in TRPV1 knockouts was rescued by activating OLM neurons with nicotine—via the a2 receptor—to bypass innervation defects
To test if TRPV1 is present in the hippocampus, we first examined TRPV1 mRNA levels in adult wild type (WT) and TRPV1 knockout animals by quantitative PCR (qPCR)

Summary

Introduction

TRPV1 is an ion channel activated by heat and pungent agents including capsaicin, and has been extensively studied in nociception of sensory neurons. TRPV1 knockouts have reduced Schaffer collateral LTP, which is rescued by activating OLM neurons with nicotine—via a2b2-containing nicotinic receptors—to bypass innervation defects. Later studies reported broad expression of TRPV1 in the brain including the hippocampus[7,8,9], where it was observed in cell bodies of pyramidal neurons throughout the CA1 and CA3 regions and the dentate gyrus of the hippocampal formation[9]. One model proposed that high-frequency stimulation of the Schaffer collateral pathway activates presynaptic TRPV1 on pyramidal neurons, which persistently reduces glutamate release onto interneurons[14]. TRPV1 was not localized in these studies, and these models are both at odds with reports of restricted expression of TRPV1 in the adult hippocampus[10] Both the presence of TRPV1 in the hippocampus—whether broadly expressed, sparsely expressed, or not at all—and how TRPV1 affects hippocampal plasticity and function, is still unclear

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