What goes up must come down: homeostatic synaptic plasticity strategies in neurological disease

Abstract

Brain activity levels are tightly regulated to minimize imbalances in activity state. Deviations from the normal range of activity are deleterious and often associated with neurological disorders. To maintain optimal levels of activity, regulatory mechanisms termed homeostatic synaptic plasticity establish desired 'set points' for neural activity, monitor the network for deviations from the set point and initiate compensatory responses to return activity to the appropriate level that permits physiological function [1,2]. We speculate that impaired homeostatic control may contribute to the etiology of various neurological disorders including epilepsy and Alzheimer's disease, two disorders that exhibit hyperexcitability as a key feature during pathogenesis. Here, we will focus on recent progress in developing homeostatic regulation of neural activity as a therapeutic tool.

Keywords: Alzheimer's disease; CA3; Plk2; antiseizure drugs; dentate gyrus; epilepsy; homeostatic synaptic plasticity; kappa opioid receptors; mossy fiber; synaptoporin.

Figure 1.. Mechanisms of homeostatic synaptic plasticity that are discussed in the text.

(A) Normal homeostatic synaptic plasticity. On the left are pathways involved in homeostatic upregulation in response to chronic hypoactivity and on the right are those involved in downregulation following persistent hyperactivity. Negative feedback compensation alters synaptic number, strength or size in order to return network activity to an optimal, balanced level. Multiple homeostatic mechanisms have been identified and only a subset is depicted here. (B) Proposed mechanisms of aberrant homeostatic plasticity that may contribute to neurological disorders. On the left is a hypothetical pathway that may promote development of epilepsy, in which an initial insult leads to a latent period of hypoactivity, triggering overcompensation and excessive synaptic strengthening due to dysfunctional homeostatic machinery that ultimately leads to seizures. Therapeutic strategies for epilepsy could be to inhibit: kappa opioid receptors or synaptoporin function to prevent development of seizures or perform closed-loop bioengineering control to terminate seizures acutely. On the right is a proposed model for pathogenesis of Alzheimer's disease in which aggregation of Aβ leads to hyperactivity of neurons rather than downregulation as in the normal condition. Hyperexcitation leads to further production of Aβ via Plk2, forming a positive feedback, amplifying loop instead of a negative feedback control system. A therapeutic approach to address this model could be to inhibit Plk2 activity and interrupt the vicious cycle.