Abstracts

Rationale: Increasing body of evidence suggests a link between stress and epilepsy, which indicates involvement of the stress-regulating hypothalamic network in pathophysiology of epilepsy. Thus we studied the role of hypothalamic nuclei in initiation and/or control of seizures. We focused on the paraventricular nucleus (PVN), ventromedial nucleus (VMH), arcuate nucleus (ARC) of the hypothalamus and lateral hypothalamus (LH), which are involved in regulation of stress response. We used our model of Infantile Spasms (IS) to address this objective. Methods: The IS model consists of prenatal priming with betamethasone and postnatal trigger of spasms by NMDA. For activation/suppression of structures we used unilateral infusion of a GABA(A) receptor agonist, muscimol (Musc), or an antagonist, bicuculline (Bic), in the target structures of prenatally-primed rats on postnatal day (PN) 15. We first monitored behavioral changes after microinfusion of GABAergic compounds in each of the hypothalamic nuclei. Then we tested effects of this activation/suppression on subsequent NMDA-triggered spasms. Results: Unilateral infusion of Musc into the PVN induced spasm-like behavior. Soon after the Musc infusion animals started curling up in a flexion position resembling the spasms observed in response to the NMDA ip injection. In contrast, Musc infusions in VMH, LH and ARC did not induce any behavioral changes. This finding indicates that overactivation of GABAergic transmission only in the PVN may lead to spasm-like phenotype. Musc infusion into the PVN, LH and ARC did not affect development of subsequent NMDA-triggered spasms, while the intra-VMH infusion of Musc had a significant anticonvulsant effect as it delayed the onset of NMDA-triggered spasms. Infusion of Bic in any of the targeted structures induced severe agitation within about 3-4 min, which disappeared within 7-8 min. Similarly to Musc, Bic infusions had diverse effects on the development of NMDA-triggered spasms. Intra-PVN infusion of Bic showed an anticonvulsant effect as it significantly decreased number of NMDA-triggered spasms. Intra-VMH infusion of Bic facilitated occurrence of NMDA-triggered spasms opposite to the effect of the intra-VMH Musc infusion. A similar proconvulsant effect on NMDA-triggered spasms was observed after Bic infusion into the LH, as it shortened the latency to onset of NMDA-triggered spasms. Intra-ARC infusion of Bic had no effect on NMDA-triggered spasms. Conclusions: Our findings identify the hypothalamic stress-regulating network as a novel candidate system involved in initiation and/or control of seizures, particularly the spasms. By activating or inhibiting structures of this network, we successfully attenuated or facilitated occurrence of NMDA-triggered spasms. Interestingly among these structures, the PVN is the only one, which can be associated with spasm-like behavioral phenotype of seizures. Thus, the hypothalamic network may serve as a potential target for new therapeutic approaches for antiseizure/antiepileptic treatments.