Mitf links neuronal activity and long-term homeostatic intrinsic plasticity

Abstract Neuroplasticity forms the basis for neuronal circuit complexity and can determine differences between otherwise similar circuits. Although synaptic plasticity is fairly well characterized, much less is known about the molecular mechanisms underlying intrinsic plasticity, especially its transcriptional regulation. We show that the Microphthalmia-associated transcription factor ( Mitf ), best known as the master regulator of melanocytic cell fate and differentiation, plays a central role in homeostatic intrinsic plasticity of olfactory bulb (OB) projection neurons. Mitral and tufted (M/T) neurons from Mitf mutant mice are hyperexcitable due to reduced Type-A potassium current (I A ) and they 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, The MITF protein binds to and activates expression from Kcnd3 regulatory elements. Activity can therefore affect Kcnd3 expression directly via MITF. 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, plays a key role in olfactory adaptation and links neuronal activity, transcriptional changes and neuronal function. Significance statement A direct, Mitf -dependent link between neuronal activity and homeostatic changes in the expression of a key potassium channel subunit is demonstrated in projection neurons of the mouse OB. This is one of the first studies that directly link activity and genetically defined changes in intrinsic plasticity, leading to changes in neuronal response. These findings broaden the general understanding of transcriptional regulation of homeostatic intrinsic plasticity in learning and memory. The results are also important for understanding the role of Mitf in other cell types. Regulation of intrinsic plasticity has wide-ranging implications and fundamental importance for neurological diseases such as neurodegeneration, autism and epilepsy.