Activity Deprivation Leads to Seizures in Hippocampal Slice Cultures: Is Epilepsy the Consequence of Homeostatic Plasticity?

Abstract

Neural networks operate robustly despite destabilizing factors, ranging from gene product turnover to circuit refinement, throughout life. Maintaining functional robustness of neuronal networks critically depends upon forms of homeostatic plasticity including synaptic scaling. Synaptic strength and intrinsic excitability have been shown to "scale" (up or down) in response to altered ambient activity levels, and this has led to the general idea that homeostatic plasticity operates along a continuum. After 48 hours of activity deprivation, cultured hippocampal networks exhibited a homeostatic-type reconfiguration that was discrete: a switch from spontaneous spiking to oscillatory bursting. Blockade of fast glutamatergic and GABAergic transmission abolished spontaneous network bursting, but the majority of neurons exhibited intrinsic bursting in response to current injection, which was not the case in control tissue. This de novo intrinsic bursting could be blocked by cadmium chloride, suggesting that this bursting involves calcium mechanisms. Immunohistochemistry confirmed that activity-deprived slice cultures exhibited a widespread upregulation of voltage-dependent calcium channels compared with controls. Calcium imaging studies from activity-deprived slices demonstrated that spontaneous bursting was not a local behavior, but rather a global, synchronous phenomenon, reminiscent of seizure activity. These data suggest that the input/output transformation of individual neurons undergoing homeostatic remodeling is more complex than simple scaling. Network consequences of this transformation include network destabilization of epileptic proportions. Spontaneous activity plays a critical role in actively maintaining homeostatic balance in networks, which is lost after activity deprivation.

Pathological Effect of Homeostatic Synaptic Scaling on Network Dynamics in Diseases of the Cortex

“…In a previous computational modeling study (Houweling et al, 2004), cortical deafferentation was simulated to examine homeostatic plasticity as a potential cause of posttraumatic epilepsy. A recent study with cultured hippocampal slices provided additional support for this hypothesis (Trasande and Ramirez, 2007). In contrast to this previous modeling work, we have now studied the time course of network reorganization after partial deafferentation to understand the specific roles of intact and deafferented cells as a function of time after disease onset.…”

Homeostatic plasticity induced by brief activity deprivation enhances long-term potentiation in the mature rat hippocampus

“…However, recovery may come at a cost. Overcompensatory effects have been associated with the generation of reverberant circuits and postlesional epileptogenesis (Fröhlich et al 2008;Trasande and Ramirez 2007;Queenan and Pak 2013). Indeed, a decrease in the threshold for Hebbian forms of plasticity may likely contribute to reinforce reverberant circuits and epileptogenesis after synapse silencing.…”

“…Prolonged (60-h) blockade of evoked glutamate release in cultured slices was recently shown to enhance the ability of the hippocampal circuitry to undergo pairing-induced LTP through silent synapse formation (Arendt et al 2013). However, application of the same activity deprivation model to cultured hippocampal slices has also been shown to trigger seizurelike activity (Trasande and Ramirez 2007) suggestive of maladaptive network reorganization (Fröhlich et al 2008). Here, we used acute slices and brief blockade of neuronal activity to address the interaction between homeostatic and Hebbian plasticity induced by TBS in a mature neuronal circuit.…”

Prostaglandin E2-Induced Synaptic Plasticity in Neocortical Networks of Organotypic Slice Cultures

“…But homeostatic mechanisms can also include alterations in synaptic inhibition (Maffei et al, 2006;Stellwagen and Malenka, 2006) or shifts in intrinsic excitability (Desai et al, 1999;Aizenman et al, 2003). Consistent with a homeostatic response, activity deprivation in hippocampal slice cultures leads to increased excitatory synaptic transmission (Trasande and Ramirez, 2007). But longterm activity deprivation strengthened excitatory synapses to the extent that the hippocampal network generated seizure-like activity, revealing a potentially dark side of homeostatic regulation (Trasande and Ramirez, 2007).…”