ALTERED EFFECTS OF EXOGENOUS OREXIN ON HIPPOCAMPAL NEURONAL ACTIVITY IN EPILEPSY

Orexins are hypothalamic neuropeptides synthesized by a discrete neuronal population with extensive projections throughout the central nervous system, where they exert broad regulatory control over physiological processes. Dysregulation of the orexinergic system has been implicated in multiple pathophysiological conditions; however, its contribution to epileptogenesis remains controversial, with evidence supporting both pro-convulsant and anticonvulsant effects. In vivo experiments were performed to investigate the effects of kainic acid–induced status epilepticus (KA-SE) on hippocampal and hypothalamic function and to assess subsequent alterations in the modulatory role of Orexin-A within the hippocampus. KA-SE rats exhibited significant cognitive and emotional impairments. In vivo 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 analyses demonstrated KA-SE–associated neuronal loss in both the hippocampus and hypothalamus, including a significant reduction of GAD-positive interneurons in the CA3 region of the hippocampus and Orexin-B–positive neurons in the hypothalamus. The loss of GAD-positive interneurons, which constitute major targets of orexinergic input within CA3, likely contributes to the impaired orexinergic modulation observed following KA-SE. Together, these findings demonstrate divergent orexinergic modulation in normal and epileptic hippocampal circuits and provide mechanistic insight into epilepsy-related alterations of synaptic and network function.