Severe childhood epilepsy is commonly associated with intellectual developmental disabilities. The reasons for these cognitive deficits are likely multifactorial and will vary between epilepsy syndromes and even among children with the same syndrome. However, one factor these children have in common is the recurring seizures they experience - sometimes on a daily basis. Supporting the idea that the seizures themselves can contribute to intellectual disabilities are laboratory result demonstrating spatial learning and memory deficits in normal mice and rats that have experienced recurrent seizures in infancy. Studies reviewed here have shown that seizures in vivo and electrographic seizure activity in vitro both suppress the growth of hippocampal pyramidal cell dendrites. A simplification of dendritic arborization and resulting decrease in the number of excitatory synapses could help explain the observed cognitive disabilities. There are a wide variety of candidate mechanisms that could be involved in seizure-induced growth suppression. The challenge is designing experiments that will help focus research on a limited number of potential molecular events. Thus far results suggest that growth suppression is NMDA receptor-dependent and associated with a decrease in activation of the transcription factor CREB. The latter result is intriguing since CREB is known to play an important role in dendrite growth. Seizure-induced dendrite growth suppression may not occur as a single process in which pyramidal cells dendrites simply stop growing or grow slower compared to normal neurons. Instead, recent results suggest that after only a few hours of synchronized epileptiform in vitro dendrites appear to partially retract. This acute response is also NMDA receptor dependent and appears to be mediated by the Ca+2/calmodulin-dependent phosphatase, calcineurin. An understanding of the staging of seizure-induced growth suppression and the underlying molecular mechanisms will likely prove crucial for developing therapeutic strategies aimed at ameliorating the intellectual developmental disabilities associated with intractable childhood epilepsy.

Neuronal networks are thought to gradually adapt to altered neuronal activity over many hours and days. For instance, when activity is increased by suppressing synaptic inhibition, excitatory synaptic transmission is reduced. The underlying compensatory cellular and molecular mechanisms are thought to contribute in important ways to maintaining normal network operations. Seizures, due to their massive and highly synchronized discharging, probably challenge the adaptive properties of neurons, especially when seizures are frequent and intense – a condition common in early childhood. In the experiments reported here, we used hippocampal slice cultures to explore the effects that recurring seizure-like activity had on the developing hippocampus. We found that developing networks adapted rapidly to recurring synchronized activity in that the duration of seizure-like events was reduced by 42% after 4 h of activity. At the same time, the frequency of spontaneous excitatory postsynaptic currents in pyramidal cells, the expression of biochemical biomarkers for glutamatergic synapses and the branching of pyramidal cell dendrites were all dramatically reduced. Experiments also showed that the reduction in N-methyl-D-aspartate receptor subunits and postsynaptic density protein 95 expression were N-methyl-D-aspartate receptor-dependent. To explore calcium signaling mechanisms in network adaptation, we tested inhibitors of calcineurin, a protein phosphatase known to play roles in synaptic plasticity and activity-dependent dendrite remodeling. We found that FK506 was able to prevent all of the electrophysiological, biochemical, and anatomical changes produced by synchronized network activity. Our results showed that hippocampal pyramidal cells and their networks adapted rapidly to intense synchronized activity and that calcineurin played an important role in the underlying processes.