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Advanced Neurology TRPM2 in neurological disorders

to those observed in BD patients can also be used . of mental disorders criteria for a MDD diagnosis, and
[98]
Finally, environmental manipulation through behavioral the duration and frequency of both depressive episodes
interventions, such as isolation rearing, or early postnatal and states of remission vary greatly among affected
stress paradigms, such as maternal separation and communal individuals [125,126] . Depression affects approximately 3.8%
nursing, has been used to induce depressive-like phenotypes of the population and is associated with an increased risk
characteristic of BD once mice reach adulthood [118,119] . of over 50% of developing a cardiovascular or metabolic
TRPM2 has not been extensively investigated in in vivo disease [124] . As a phenomenon characterized by symptoms
BD models; however, the outlined mouse models may be ranging from low mood, anhedonia, and fatigue to
employed in future to elucidate its contribution. psychomotor disturbances, psychotic delusions, and
Nevertheless, TRPM2 remains a priority candidate disrupted circadian rhythms, the underlying etiology
for BD because it is located in a BD susceptibility locus at is multifactorial and incompletely understood [125] . The
21q22.3 [120] . An independent fine mapping study of 21q22.3 initial and perhaps most common mechanism suggested
revealed association between TRPM2 and BD which was for depression is the monoamine hypothesis, which posits
confirmed by family-based association studies [120-122] . Ten that an imbalance of monoamine neurotransmitters,
single-nucleotide polymorphisms in TRPM2 have since including serotonin, norepinephrine, and dopamine, leads
been identified that confer increased risk of BD [122,123] . The to the development of depression [127,128] . Thus, commonly
relevance and specific contributions of these TRPM2 variants prescribed antidepressants include monoamine oxidase
to BD are seemingly based on the channel’s regulation of inhibitors and selective serotonin reuptake inhibitors.
Ca homeostasis and sensitivity to oxidative stress, both More recent investigation into the pathophysiology of
2+
of which are dysregulated under BD conditions. Elevated depression, however, has implicated abnormal functioning
oxidative stress in primary rodent neurons increases Trpm2 of the hypothalamic-pituitary-adrenal (HPA) axis,
mRNA levels and alters TRPM2 levels, while elevated deficiency of neurotrophic factors, such as brain-derived
2+
intracellular Ca levels were reported in B lymphoblast neurotrophic factor, neuroinflammation, and chronic
cell lines from BD patients [26,32,97] . Furthermore, monensin- stress, leading to decreased neurogenesis, suppressed
treated human olfactory neuroepithelial-derived progenitors cell proliferation, and an imbalance between antioxidant
have upregulated TRPM2 expression, elevated intracellular defense and free radical production within the cell [127,129,130] .
calcium levels, as well as increased caspase-3, caspase-7, To elucidate the contributions of these molecular
and PARP; effects were attenuated by lithium treatment, mechanisms and to identify key contributing molecules
the first-line treatment for BD . Interestingly, lithium in depression pathology, mouse models bred to induce
[98]
protects against oxidative stress and also inhibits GSK3 depressive-like behavior are used. The chronic unpredictable
activity. In relation to this, TRPM2 mice have increased stress (CUS) model is one of the most commonly employed
-/-
protein levels of the inactivated phosphorylated GSK3α and involves exposure of the rodent to a battery of mild,
and GSK3β, while the stimulation of TRPM2 leads to a variable stressors daily for 4 – 12 weeks, ultimately leading
downregulation of GSK3 phosphorylation. Furthermore, to depressive-like behavior including reduced sucrose
-/-
TRPM2 mice exhibited BD-related behavior, including preference, and increased immobility on the forced swim
increased anxiety and decreased sociability, and treatment test and learned helplessness test [131,132] . The social isolation,
with lithium was ineffective in attenuating these behavioral chronic social defeat stress, and learned helplessness
deficits . Together, these results indicate that genetic models are also frequently used and involve exposure
[99]
variants of TRPM2 may lead to abnormal regulation of to psychosocial and physical stressors, respectively [132] .
GSK3, a primary target of the BD treatment, lithium, thereby Mice with impaired glucocorticoid functioning to induce
inducing behavioral abnormalities associated with manic an overactive HPA axis, such as glucocorticoid receptor
and depressive states. Further study is required, however, to [133]
identify whether targeting TRPM2 alone or in conjunction knockout mice, also exhibit depressive symptoms .
with other BD-relevant interventions can protect against Inflammation and oxidative stress have emerged as
both manic and depressive episodes in the long term. central mediators in psychopathology. Specifically, increased
serum levels of IL-1β and TNF-α are positively correlated
4.2. Depression with the severity of depression in MDD patients, while a
Depression is a leading cause of disability worldwide. It meta-analysis of clinical trials demonstrated that anti-
adversely affects workplace productivity and has a profound inflammatory drugs concurrently confer antidepressant
socioeconomic impact at both personal and organizational effects [134,135] . Further, markers of oxidative stress, including
levels [124] . Depression is heterogeneous with ~256 unique 8-hydroxy-2′-deoxyguanosine and NADPH oxidases,
symptoms meeting the diagnostic and statistical manual a family of ROS-generating enzymes, are significantly

Volume 1 Issue 1 (2022) 10 https://doi.org/10.36922/an.v1i1.3