New Insights into Epileptic Spasm Generation and Treatment from the TTX Animal Model

Abstract

Currently, we have an incomplete understanding of the mechanisms underlying infantile epileptic spasms syndrome (IESS). However, over the past decade, significant efforts have been made to develop IESS animal models to provide much-needed mechanistic information for therapy development. Our laboratory has focused on the TTX model, in which tetrodotoxin (TTX) is infused into the neocortex of infant rats, producing a lesion at the infusion site and mimicking IESS resulting from acquired structural brain abnormalities. Subsequent electrophysiological studies showed that the epileptic spasms originate from neocortical layer V pyramidal cells. Importantly, experimental maneuvers that increase the excitability of these cells produce focal seizures in non-epileptic control animals but never produce them in TTX-infused epileptic rats; instead, epileptic spasms are produced in epileptic rats, indicating a significant transformation in the operations of neocortical networks. At the molecular level, studies showed that the expression of insulin-like growth factor 1 was markedly reduced in the cortex and this corresponded with a loss of presynaptic GABAergic nerve terminals. Very similar observations were made in surgically resected tissue from IESS patients with a history of perinatal strokes. Other experiments in conditional knockout mice indicated that IGF-1 plays a critical role in the maturation of neocortical inhibitory connectivity. This finding led to our hypothesis that the loss of IGF-1 in epileptic animals impairs inhibitory interneuron synaptogenesis and is responsible for spasms. To test this idea, we treated epileptic rats with the IGF-1-derived tripeptide (1-3)IGF-1, which was shown to act through IGF-1s receptor. (1-3)IGF-1 rescued inhibitory interneuron connectivity, restored IGF-1 levels, and abolished spasms. Thus (1-3)IGF-1 or its analogues are potential novel treatments for IESS following perinatal brain injury. We conclude by discussing our findings in the broader context of the often-debated final common pathway hypothesis for IESS. We confirm that we have read the Journals position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Plain Language SummaryWe review recent findings from the TTX animal model of infantile epileptic spasms syndrome, which show that these seizures come from an area of the brain called the neocortex. In this area, the amount of an important growth factor called IGF-1 is reduced, as is the number of inhibitory synapses that play an important role in preventing seizures. Other results indicate that the loss of IGF-1 prevents the normal development of these inhibitory synapses. Treatment of epileptic animals with (1-3)IGF-1 restored IGF-1 levels and inhibitory synapses and abolished spasms. Thus, (1-3)IGF-1 or an analogue are potential new therapies for epileptic spasms.