Mitf Links Neuronal Activity and Long-Term Homeostatic Intrinsic Plasticity

Abstract

Neuroplasticity forms the basis for neuronal circuit complexity and differences between otherwise similar circuits. We show that the microphthalmia-associated transcription factor (Mitf) plays a central role in intrinsic plasticity of olfactory bulb (OB) projection neurons. Mitral and tufted (M/T) neurons from Mitf mutant mice are hyperexcitable, have a reduced A-type potassium current (I A) and exhibit reduced expression of Kcnd3, which encodes a potassium voltage-gated channel subunit (Kv4.3) important for generating the I A. Furthermore, expression of the Mitf and Kcnd3 genes is activity dependent in OB projection neurons and the MITF protein activates expression from Kcnd3 regulatory elements. Moreover, Mitf mutant mice have changes in olfactory habituation and have increased habituation for an odorant following long-term exposure, indicating that regulation of Kcnd3 is pivotal for long-term olfactory adaptation. Our findings show that Mitf acts as a direct regulator of intrinsic homeostatic feedback and links neuronal activity, transcriptional changes and neuronal function.

Absence of meningeal mast cells in the Mitf mutant mouse

“…While two copies of Mitf are required for a normal number of MCs, this suggests a tissue-dependent Mitf dosage effect or defects in maintaining MCs in heterozygotes. This is in accordance with known haploinsufficiency in Mitf mutant mice (Harris et al, 2018;Atacho et al, 2020;Han et al, 2020). Increased inflammation is central to CNS pathologies.…”

“…MITF is a basic helix-loop-helix leucine zipper transcription factor that plays a critical role in the development of many cell types (Hemesath et al, 1994;Steingrimsson et al, 2004), including melanocytes, retinal pigment cells, osteoclasts, and a subpopulation of CNS neurons (Nakayama et al, 1998;Steingrimsson et al, 2002;Gudjohnsen et al, 2015;Atacho et al, 2020). The Mitf gene has been shown to be both important for the generation (Kitamura et al, 2002;Sasaki et al, 2016;Ingason et al, 2019) and function of MCs (Morii et al, 1996(Morii et al, , 1997Nechushtan and Razin, 2002;Paruchuru et al, 2022).…”

Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients

“…In accordance with these results, gene MITF (melanocyte inducing transcription factor) was upregulated by 2.5-fold in NR neurons treated with VPA compared to CTL neurons (padj <0.0076). MITF was recently described as a regulator of neuronal activity by transcriptional activation of Kv4.3 potassium channel in olfactory bulb projection neurons [ 71 ].…”

“…In our study, we found that treatment of NR neurons with VPA caused a change in transcription of the genes involved in synaptic activity and voltage-gated channels. Interestingly two of these genes, MITF and KCNH3 , encode regulators of excitability [ 70 , 71 ]. This study and our previous studies [ 43 , 44 ] showed that hyperexcitability of BD DG-like neurons was a reproducible phenotype that correlated with clinical response of patients to medication.…”

User guide to MiT‐TFE isoforms and post‐translational modifications

“…MITF has emerged as a key regulator of proliferation, differentiation, cell cycle, and survival of melanocytes and melanoma cells (reviewed in Goding & Arnheiter, 2019). It also affects mast cells, retinal pigment epithelium (RPE) and osteoclast development and in addition plays a role in olfaction as well as in circadian regulation of gene expression (Atacho et al, 2020; Malcov‐Brog et al., 2018; Morii et al., 1996; Shibahara et al., 2000; Weilbaecher et al., 2001). In humans, MITF mutations have been linked to Tietz syndrome (Amiel, Watkin, Tassabehji, Read, & Winter, 1998; Smith, Kelley, Kenyon, & Hoover, 2000), Waardenburg syndrome type 2A (Tassabehji, Newton, & Read, 1994) as well as the more serious COMMAD syndrome observed in individuals carrying MITF mutations on each of the two chromosomes (George et al., 2016).…”