Mitf links neuronal activity and long-term homeostatic intrinsic plasticity.

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 Type-A 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 habitutation for an odourant 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.Significance statement These findings broaden the general understanding of transcriptional regulation of intrinsic plasticity in learning and memory. Regulation of intrinsic plasticity has wide-ranging implications and fundamental importance for neurological diseases.