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Advanced Neurology TRPM2 in neurological disorders

free-falling weight and injury severity largely depends depressive episodes. These states vary in duration from
on the mass and the height of the weight . Of the three weeks to several months and are accompanied by changes
[92]
major weight drop injury variations, Marmarou’s impact in energy levels as well as cognitive, behavioral, and physical
acceleration model differs in that it involves linear and symptoms [102] . A manic episode may be accompanied by
rotational acceleration to cause diffuse head injury. This an elevated or irritable mood, psychomotor agitation,
model represents TBIs that occur due to traffic accidents grandiosity, racing thoughts, and sleep loss. Depressive
and falls, generating widespread neuronal damage and symptoms include reduced interest in all activities,
diffuse axonal injury in cortical and subcortical regions . psychomotor retardation, fatigue, impaired concentration
[92]
Last, sports injury can be modeled with repeated mild or indecisiveness, and suicide ideation [102,103] . Globally, BD
TBI, and combat-related brain injury can be modeled with has a median age of onset of ~25 years, a lifetime prevalence
blast-induced or penetrating ballistic-like brain injury. of 0.4 – 0.6%, and is associated with high morbidity,
mortality, and socioeconomic burden [104] .
The role of TRPM2 in TBI has been investigated
in rodents in two studies [94,95] . Both used the impact Although etiological roles for common variant alleles
acceleration model in male rats. Compared with are well-established, rare variants and epigenetic factors
sham-operated rats, TRPM2 was transcriptionally and may also contribute to underlying BD pathophysiology
translationally upregulated in the cortex and hippocampus and phenotypic presentation of the disorder [105] . Various
of rats subjected to TBI . The upregulation of TRPM2, interrelated molecular mechanisms have been postulated
[95]
however, was not observed until 3 days post-TBI while the to underlie BD. These include cyclic dysregulation of
[95]
expression remained elevated at 5 days post-TBI . These dopaminergic transmission, altered ionic homeostasis and
findings indicate that delayed and prolonged activation of calcium metabolism, and chronic inflammation in both
TRPM2 contributes to injury following TBI. Another study the periphery and brain with increased levels of IL-1β,
reported that modulation of TRPM2 by the antioxidant IL 1 receptor, nuclear factor kappa B, and glial fibrillary
melatonin reduced caspase-3-dependent apoptosis and acidic protein mRNA and protein in the post-mortem
ROS accumulation in hippocampal neurons through the frontal cortex of BD patients. Mitochondrial dysfunction
regulation of (TRPM2-mediated) Ca entry . and oxidative stress have also been suggested to play
2+
[94]
important roles as indicated by reduced expression of
Further studies are required to investigate TRPM2 mitochondrial ETC complex I subunits and increased
action over multiple time points following TBI. Since oxidative and nitrosative damage in BD brains [106-109] . Given
differences in males and females have been demonstrated its role in regulating intracellular Ca homeostasis and
2+
in TRPM2-mediated acute brain injury, with a trend of oxidative stress, TRPM2 has been implicated in mediating
increased susceptibility in males after experimental TBI , BD-related pathophysiological disturbances [110] .
[96]
it will be interesting to include both sexes in future TBI
studies to examine sex-dependent TRPM2 responses. To study the role of TRPM2 in BD using rodent models,
genetic, pharmacological, and environmental manipulation
The studies discussed in section 3 are summarized in may be employed. Mutations in the circadian locomotor
Table 1. output cycles kaput gene have induced manic- and depressive-

4. TRPM2 in psychiatric disorders like behaviors in mice, as has genetic ablation of DAT [111,112] .
DAT knockdown mice exhibit photoperiod length-driven
Recent genome-wide association studies have implicated manic- and depression-relevant behaviors including
TRPM2 in psychiatric disorders. The responsiveness of enhanced risk preferring behavior (manic) in long-active
TRPM2 to oxidative stress and the key role this channel photoperiods and enhanced punishment sensitivity and
plays in mediating intracellular calcium homeostasis despair-related behavior (depression) during short-active
and neuroinflammation makes it an attractive candidate photoperiods [113] . This mimics seasonally induced switching
in disease etiology and supports its relevance in mood of states – summer-onset mania and winter-onset depression
disorders and mental illness. Specifically, TRPM2 is a – that parallel the switch between mania and depression
potential therapeutic target in bipolar disorder (BD) and characteristic of BD. Viral-mediated over- and under-
major depressive disorder (MDD). Current models used to expression of the dopamine D1 receptor is also associated
study these disorders and the contribution of TRPM2 to with manic and depressive phenotypes, respectively [114] .
their distinct pathology are discussed below. Furthermore, administration followed by subsequent
withdrawal of psychostimulants, including amphetamine,
4.1. BD fenproporex, and cocaine [115-117] , may be used to mimic BD
BD is a complex psychiatric disorder with clinical in mice, while compounds such as monensin that acts to
heterogeneity characterized by recurrent manic and elevate intracellular Na concentration to levels comparable
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Volume 1 Issue 1 (2022) 8 https://doi.org/10.36922/an.v1i1.3