The Role of the Transient Receptor Potential Vanilloid 1 (TRPV1) Channel in Sharp Wave Ripples, Place Cells, and Spatial Memory
by Chrystalleni Vassiliou
Date of Examination:2023-02-09
Date of issue:2024-02-09
Advisor:Dr. Camin Dean
Referee:Dr. Camin Dean
Referee:Prof. Dr. Hansjörg Scherberger
Referee:Prof. Dr. Tobias Moser
Referee:Dr. Brett Carter
Referee:Dr. Caspar M. Schwiedrzik
Referee:Prof. Dr. Dr. Oliver Schlüter
Persistent Address:
http://dx.doi.org/10.53846/goediss-10345
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Abstract
English
Previous research in our lab found impaired long-term potentiation (LTP) of CA3-CA1 synapses, a fundamental process for learning and memory, in transient receptor potential vanilloid 1 (TRPV1) knockout (KO) mice. The TRPV1 channel is specifically expressed in oriens lacunosum moleculare (OLM) interneurons in the hippocampus, where it controls their excitatory innervation. OLM neurons participate in sharp wave ripples (SWRs), another phenomenon known for its importance in memory consolidation. During SWRs, which occur during sleep and rest, neuronal firing sequences representing a previous waking experience are reactivated, leading to consolidation of the memory by strengthening the connections between firing neurons, i.e., LTP. We therefore hypothesized that TRPV1 KO mice will have impaired SWRs, mirroring LTP deficits. The TRPV1 channel is activated by a multitude of signals, including temperature, which decreases during sleep, when SWRs occur. We therefore first studied SWRs in hippocampal slices at different temperatures. Slices from TRPV1 KO mice had enhanced SWRs, with the most prominent effect being increased duration and rate of occurrence at 36 oC. We then examined SWRs in vivo in behaving mice during rest periods before and after exploration of two open fields, and saw a similar enhancement of SWRs, this time manifested as increased ripple magnitude and frequency. Theta oscillations, which are involved in memory encoding, had a higher frequency but lower power in TRPV1 KO mice, and delta oscillations were also affected. Spatial tuning was impaired in TRPV1 KO mice, as place cells had larger place fields and were less stable than in wild-type (WT) mice. Memory was examined using the cheeseboard maze task. Both WT and TRPV1 KO mice learned the first reward location at similar rates, but KO mice took longer to reach a new reward when its location was moved. This could hint at an impairment in memory extinction, but further analysis is required to confirm this. SWRs can transform into epileptiform discharges and pathological ripples. Febrile seizures develop in young children due to fever, and since the TRPV1 channel is temperature sensitive, we hypothesized it might alter susceptibility to seizure induction. Temperature elevation increased epileptiform activity (EA) in a similar percentage of slices from young WT and TRPV1 KO mice. However, a lower percentage of TRPV1 KO slices had EA at 31 oC, consistent with a protective effect of TRPV1 inhibition in seizure susceptibility. Another goal of this study was to investigate the relationship between LTP and SWRs. High-frequency stimulation (HFS) that induces LTP increased SW duration, but decreased SW incidence. Anisomycin, which blocks protein synthesis and LTP maintenance, had no effect on SWRs. SAHA, which on the other hand enhances LTP, had only minimal effects on SWRs with short-term application, and decreased SWRs with long-term application, possibly due to excitotoxicity. Our results suggest that SWRs and LTP are therefore not always positively correlated. LTP and SWRs are impaired in Alzheimer’s disease (AD), the most prominent type of dementia. Tau aggregation is a hallmark of AD pathogenesis and tau application on slices causes LTP deficits. We tested SWRs in the presence of tau, and found that tau oligomers only moderately affect SWRs, while larger tau aggregates significantly reduced SWRs in hippocampal slices, consistent with SWR changes in AD mouse models and subsequent learning and memory deficits. In summary, we provide evidence that the TRPV1 channel is involved in hippocampal SWRs, theta and delta oscillations, place cell spatial tuning, and possibly memory extinction, and expand knowledge of the association between SWRs and LTP in normal and pathological states.
Keywords: TRPV1; Sharp-wave ripples; Hippocampal oscillations; Place cells; Memory
