Homeostatic Plasticity in Epilepsy

Abstract

In the healthy brain, neuronal excitability and synaptic strength are homeostatically regulated to keep neuronal network activity within physiological boundaries. Epilepsy is characterized by episodes of highly synchronized firing across in widespread neuronal populations, due to a failure in regulation of network activity. Here we consider epilepsy as a failure of homeostatic plasticity or as a maladaptive response to perturbations in the activity. How homeostatic compensation is involved in epileptogenic processes or in the chronic phase of epilepsy, is still debated. Although several theories have been proposed, there is relatively little experimental evidence to evaluate them. In this perspective, we will discuss recent results that shed light on the potential role of homeostatic plasticity in epilepsy. First, we will present some recent insights on how homeostatic compensations are probably active before and during epileptogenesis and how their actions are temporally regulated and closely dependent on the progression of pathology. Then, we will consider the dual role of transcriptional regulation during epileptogenesis, and finally, we will underline the importance of homeostatic plasticity in the context of therapeutic interventions for epilepsy. While classic pharmacological interventions may be counteracted by the epileptic brain to maintain its potentially dysfunctional set point, novel therapeutic approaches may provide the neuronal network with the tools necessary to restore its physiological balance.

Keywords: REST (RE-1 silencing transcription factor); epilepsy; excitation inhibition balance; gene therapy; homeostatic plasticity; synaptic transmission.

Figure 1

Graphical representation of the potential role of homeostatic plasticity in the epileptic process. The blue box represents the physiological space (Asymptomatic Area) in which homeostatic plasticity, operating within the limits of physiological condition, is still able to counteract changes in neuronal activity to reset the correct setpoint. The light red box represents the pathological space (Symptomatic Area), in which homeostatic plasticity has failed or even aggravate the network state. Gene therapy interventions (orange arrow) can reset the physiological set point in the chronic phase of epilepsy probably “boosting” the inefficient homeostatic plasticity. Representative heatmaps represent gene expression in physiological and pathological conditions, where blue is gene downregulation and red is gene upregulation.