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Mechanisms of Homeostatic Control of Neuronal Intrinsic Excitability


A neuron’s identity and function are dictated by its electrophysiological signature. The firing pattern of a neuron emerges from the particular combination of ion channels in its membrane. A neuron can “tune” the combination of ionic conductances that it expresses to return back to its target excitability when faced with changing conditions. While this phenomenon of firing rate homeostasis (FRH) is well-established, the mechanisms underlying it have remained mysterious. A prevalent theory proposes that firing rates are maintained through regulatory feedback relying on the detection and stabilization of a single variable, calcium. Within the framework of this theory, all perturbations with equivalent effects on neuronal activity should invoke the same homeostatic response. In a direct test of this hypothesis, we compared two independent experimental manipulations to the Shal potassium ion channel. While we observed FRH following either a conductance-blocking mutation or complete elimination of the Shal protein, the compensating currents and the molecular mechanisms underlying the homeostatic response differed between the two conditions. Neurons lacking the Shal protein enacted transcriptional upregulation of the ion channels Slo, Shab, and Shaker, in part through the transcription factor Krüppel. In contrast, neurons with a non-conducting Shal channel compensated through non-transcriptional modification of a different set of conductances. We propose that neurons have multiple, separable homeostatic signaling systems, including proteostatic and activity-sensitive feedback systems. We then further expand on the mechanisms of FRH to include a role for the Notch signaling system. This canonical pathway for neural development is reactivated following loss of Shal and is necessary for stabilization of firing rates. We propose a model in which the loss of the transcription factor Nerfin-1 de-represses the Notch, and Notch cleavage by presenilin followed by cooperation of NICD with Su(H) results in transcriptional rebalancing of ion channels. These findings have implications for the pathophysiology of human channelopathies and Alzheimer’s disease.

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