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.

REST/NRSF drives homeostatic plasticity of inhibitory synapses in a target-dependent fashion

“…The brain is characterized by a constant and fine homeostatic regulation of neuronal intrinsic excitability and synaptic strength aimed at keeping neuronal networks’ activity within a physiological range. The dysregulation of such homeostatic mechanisms is implicated in the early-phase progression of several neurological disorders, including epilepsy and Alzheimer’s disease (Frere and Slutsky, 2018; Lignani et al, 2020; Styr and Slutsky, 2018). An increasing amount of experimental evidence shows that the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is the molecular hub of a complex neuronal transcriptomic remodeling aimed at maintaining brain homeostasis (Zullo et al , 2019; Lu et al , 2014; Hu et al , 2011; Pozzi et al , 2013; Pecoraro-Bisogni et al , 2018).…”

mir124-dependent tagging of glutamatergic synapses by synaptopodin controls non-uniform and input-specific homeostatic synaptic plasticity

“…Together, these results suggest that HSP induced by activitydeprivation at the network level alters synaptic strengths distribution and profoundly affects the rules for individual synapses to undergo Hebbian plasticity and to functionally interact together (Lee and Kirkwood, 2019), with possible consequences for synaptic circuit development (Tien and Kerschensteiner, 2018) and the formation of memory engrams (Lee and Kirkwood, 2019; Mendez et al, 2018). In particular, non-uniform HSP resulting from network-wide activity alterations could become maladaptive in some pathological contexts such as Alzheimer disease and epilepsy where it may be achieved at the expense of synaptic input integration and plasticity (Galanis and Vlachos, 2020; Li et al, 2019; Lignani et al, 2020; Styr and Slutsky, 2018).…”

Synaptic Vesicles Dynamics in Neocortical Epilepsy

“…Taken together, our results suggest a complex landscape of molecular and ultrastructural changes evolving over time, opening intriguing questions regarding the temporal evolution of homeostatic changes in response to the induction of hyperexcitability. It would be particularly interesting to observe how homeostatic regulation of excitability adapts over development, for example in a model of genetic epilepsy, where epileptogenic factors are present since the very early formation of the nervous system ( Lignani et al, 2020 ). Since TeNT-induced epilepsy is pharmacoresistant ( Nilsen et al, 2005 ) and refractory seizures represent a major unmet medical need, drugs acting on CPE levels and other regulators of synaptic pools warrant further investigation as possible therapeutic treatments in currently intractable epilepsy.…”