Abstract
Purpose :
15q13.3 microdeletion syndrome is characterized by a broad spectrum of psychiatric disorders. Seven genes are located in the target region of chromosome 15 (MTMR10, FAN1, TRPM1, MIR211, KLF13, OTUD7A, and CHRNA7). While the contributions of several of the genes to the disorder have been studied using mutant mouse models, no single mouse model has been able to recapitulate the whole behavioral spectrum of human 15q13.3 microdeletion syndrome. Trpm1, one of the genes located in the target region of 15q13.3 microdeletion syndrome, has been implicated as a retinal ON bipolar cell visual signal transduction channel. Trpm1 has not been investigated concerning this syndrome because the visual impairment in Trpm1-/- mice may confound the results of behavioral tests involving vision. Emphasizing non-visual behaviors, we performed a comprehensive behavioral test battery using Trpm1 null mutant mice to examine the relationship between TRPM1 and 15q13.3 microdeletion syndrome.
Methods :
Trpm1-/- mice were generated as described previously [Koike, et al, PNAS 2009]. Mice used for behavioral test battery were housed as pairs of Trpm1-/- and WT mice. Brain weight measurement and monoamine quantification in brain tissues were performed with 129 Sv/Ev males at 4 months or 1 month. Gene expression analysis was performed with 129 Sv/Ev male mice at 1 month. Mice used for monoamine quantification were housed in pairs of Trpm1-/- mice and WT mice, and tissue dissection was performed at the same time-point.
Results :
Trpm1-/- mice exhibit abnormal behaviors that may explain some phenotypes of 15q13.3 microdeletion syndrome: including reduced anxiety-like behavior, abnormal social interaction, attenuated fear memory, and, most prominently, hyper locomotor activity. While the ON visual transduction pathway is impaired in Trpm1-/- mice, we did not detect compensatory higher sensitivities for other sensory modalities. The pathway for visual impairment is the same between Trpm1-/- mice and mGluR6-/- mice, but hyper locomotor activity has not been reported in mGluR6-/- mice. Unexpectedly, the data suggest that the phenotype of Trpm1-/- mice extends beyond that predicted from visual impairment alone.
Conclusions :
We present the first evidence associating TRPM1 with impairment of cognitive function similar to that observed in phenotypes of 15q13.3 microdeletion syndrome.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.