Mice with mutations in Trpm1, a gene in the locus of 15q13.3 microdeletion syndrome, display pronounced hyperactivity and decreased anxiety-like behavior

Tesshu Hori,Satoko Hattori,Keizo Takao,Shohei Ikuta,Tsuyoshi Miyakawa,Chieko Koike

doi:10.1186/s13041-021-00749-y

Abstract

The 15q13.3 microdeletion syndrome is a genetic disorder characterized by a wide spectrum of psychiatric disorders that is caused by the deletion of a region containing 7 genes on chromosome 15 (MTMR10, FAN1, TRPM1, MIR211, KLF13, OTUD7A, and CHRNA7). The contribution of each gene in this syndrome has been studied using mutant mouse models, but no single mouse model recapitulates the whole spectrum of human 15q13.3 microdeletion syndrome. The behavior of Trpm1−/− mice has not been investigated in relation to 15q13.3 microdeletion syndrome due to the visual impairment in these mice, which may confound the results of behavioral tests involving vision. We were able to perform a comprehensive behavioral test battery using Trpm1 null mutant mice to investigate the role of Trpm1, which is thought to be expressed solely in the retina, in the central nervous system and to examine the relationship between TRPM1 and 15q13.3 microdeletion syndrome. Our data demonstrate that 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 the most prominent phenotype of Trpm1 mutant mice, hyperactivity. While the ON visual transduction pathway is impaired in Trpm1−/− mice, we did not detect compensatory high sensitivities for other sensory modalities. The pathway for visual impairment is the same between Trpm1−/− mice and mGluR6−/− mice, but hyperlocomotor activity has not been reported in mGluR6−/− mice. These data suggest that the phenotype of Trpm1−/− mice extends beyond that expected from visual impairment alone. Here, we provide the first evidence associating TRPM1 with impairment of cognitive function similar to that observed in phenotypes of 15q13.3 microdeletion syndrome.

Highlights

TRPM1, the first member of the melanoma-related transient receptor potential (TRPM) subfamily to be discovered, is the visual transduction channel downstream of metabotropic glutamate receptor 6 in retinalON bipolar cells (BCs) [1, 2]
TRPM1 is located in human chromosome 15q13.3, a region associated with 15q13.3 microdeletion syndrome, which is a genetic disorder caused by the deletion of a ~1.5 megabase region from break-point 4 to break-point 5, comprising 7 genes: Myotubularin-related protein 10 (MTMR10); Fanconi-associated nuclease 1 (FAN1); TRPM1; MicroRNA 211 (MIR211); Hori et al Mol Brain (2021) 14:61
Humans with 15q13.3 microdeletion syndrome exhibit a spectrum of neurobehavioral phenotypes

Summary

Introduction

TRPM1, the first member of the melanoma-related transient receptor potential (TRPM) subfamily to be discovered, is the visual transduction channel downstream of metabotropic glutamate receptor 6 (mGluR6) in retinalON bipolar cells (BCs) [1, 2]. Humans with an autosomal recessive form of complete congenital stationary night blindness show mutations in TRPM1 and Trpm mutant mice exhibit the lack of a b-wave in electroretinograms and the absence of light responses in ON BCs [3]. The prevalence of 15q13.3 microdeletion syndrome is estimated to be 0.02% in otherwise healthy individuals [5]. Individuals with 15q13.3 microdeletion syndrome may present with mild to moderate intellectual disability, mild learning delays, autism spectrum disorder, epilepsy (recurring seizures), attention-deficit/hyperactivity disorder (ADHD), schizophrenia, bipolar disorder, and visual impairment [7, 11, 12]. The phenotype of 15q13.3 microdeletion syndrome is complex and heterogeneous [12, 13]; the prevalence of developmental delay or intellectual disability in these patients is higher than 80%, whereas that of hyperactivity or attention deficit disorder is approximately 10% to 20%

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