Abstracts

Rationale: The transient receptor potential vanilloid type 1 (TRPV1) receptor is a non-selective cationic channel that is activated by both chemical (capsaicin, low pH) and physical (>42^oC temperatures) nociceptive stimuli in primary sensory neurons. Increasing evidence suggests that TRPV1 receptors may play an important role in seizure genesis. TRPV1 receptors are expressed in the hippocampus and dentate gyrus, areas of the brain critically involved in seizure genesis. Activation of TRPV1 receptors is associated with calcium influx, increased firing rate and glutamate release. This has been shown to affect the release of GABA, dopamine and other catecholamines; effects that enhance synaptic efficacy and may therefore be important to seizure genesis. Recent studies in adult rodents demonstrate that TRPV1 receptor activation can have both pro- and anti-convulsant effects in various seizure models; however, it is not known whether TRPV1 is involved in febrile seizure (FS) genesis during development. Methods: In this study, we used the TRPV1-KO mouse to characterize the role of the TRPV1 receptor in FS genesis during development. TRPV1-KO and C57BL/6 (wild-type) pups were subjected to hyperthermia-induced seizure (HS) at postnatal days (P) 8, 10, 12, 15 and 20. To induce HS, the pups were fitted with a fine thermocouple for continuous measurement of rectal temperature and placed in a Plexiglas box, through which warm, dry air (45-50^oC) was circulated using a standard two-speed hair dryer. The pups remained in the box until generalized convulsion occurred, and then were immediately transferred to a cool surface where they were allowed to recover. The threshold body temperature (T_body) for HS, seizure latency and time to recovery were recorded and the rate of change in T_body from the start of hyperthermia until recovery was plotted for each pup. Results: The threshold T_body was significantly lower in TRPV1-KO compared to C57BL/6 pups at P10 (-0.8^oC; p=0.03), P12 (-1.0^oC; p=0.017) and P15 (-1.8^oC; p<0.001). TRPV1-KO pups in general required a smaller change in T_body for generalized convulsion to occur compared to C57BL/6 pups (p=0.015), but the difference was only statistically significant at P10 (1.6^oC; p=0.006). Whereas the seizure latency increased with age in C57BL/6 pups (P20>P8, 10, 12, 15; p<0.001), seizure latency did not change with age in TRPV1-KO pups (p>0.05), and was reduced ~2-fold in TRPV1-KO compared to C57BL/6 pups at P20 (p<0.001). The rate of change in T_body was also 1.3 - 1.5 fold faster in TRPV1-KO compared to control pups at P20 (p<0.001). Conclusions: This study shows that absence of the TRPV1 receptor increases the susceptibility to experimental FS in an age dependent manner during development. Further studies are needed to examine the exact mechanisms by which TRPV1 receptors are implicated in the pathogenesis of FS.