Kainic acid status epilepticus - induced changes in the hippocampus and hypothalamus alter the effects of exogenous Orexin-A in the hippocampus

This study examined the effects of kainic acid-induced status epilepticus (KA-SE) on hippocampal and hypothalamic function, and evaluated the consequent alterations in the modulatory role of Orexin-A in the hippocampus. Behavioral experiments revealed cognitive and emotional impairments in KA-SE rats. <i>In vivo</i> electrophysiological recordings demonstrated a marked reduction in electrically evoked potentials (EEPs) in the CA1 region of KA-SE rats. Application of Orexin-A enhanced EEPs amplitude in CA1 and reduced it in CA3 of control animals, but elicited no effect in KA-SE rats. Orexin-A had no significant effects on the paired-pulse facilitation of EEPs in both the control and KA-SE groups indicating postsynaptic locus of its action. Morphological analysis demonstrated KA-SE-related neuronal loss in both the hippocampus and hypothalamus, including a significant reduction of GAD-positive interneurons in the CA3 of the hippocampus and Orexin-B-positive neurons in the hypothalamus. The observed reduction in GAD-positive neurons, which represent major targets of orexinergic input within the CA3 field, likely contributes to the impaired orexinergic modulation revealed in KA-SE animals. Our study reveals divergent orexinergic modulation in normal and epileptic hippocampal circuits, providing mechanistic insight into epilepsy-induced alterations of synaptic function.