Mitf links neuronal activity and long-term homeostatic intrinsic plasticity

Neuroplasticity forms the basis of neuronal circuit functional complexity and can determine differences between otherwise similar neuronal 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 here 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 (IA) and they exhibit reduced expression of Kcnd3 (Kv4.3), which encodes a potassium voltage-gated channel subunit important for the generation of the IA. Furthermore, Mitf gene expression is activity-dependent in the OB and its absence leads to the loss of activity-dependent transcription of Kcnd3 in 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 increased olfactory discriminatory ability and, unlike wild type mice, have reduced ability to detect odour following long-term odour exposure, indicating that regulation of Kcnd3 is pivotal for the ability to recover from prolonged odour exposure. 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.