Neuronal integrity of the hippocampus is important for acquisition of memory and cognitive abilities. Neuronal degeneration occurs in the hippocampus in numerous pathological conditions such as temporal lobe epilepsy (TLE), focal brain ischemia, Alzheimer's disease. In TLE, the hippocampal circuitry and neurochemical milieu are affected to the extent that this condition presents as a series of clinical sequelea including learning and memory disabilities which compound the spontaneous and sometimes severe seizures. Glutamate is the principle transmitter of hippocampal circuitry and multiple glutamate receptor subtypes exist to mediate its synaptic actions. Excitatory inputs and a series of intrinsic excitatory connections are severely compromised in certain epilepsies rendering a hyperexcitable, cell impoverished hippocampal infrastructure which reorganizes by aberrant sprouting and foreign connections. The goals of the proposal are: A. In spite of the importance of hippocampal circuitry in hyperexcitability, recurrent seizures and reorganization changes, studies to address these issues have not been performed. Using the kainate model of TLE, the applicants will address the issue of glutamatergic deafferentation by instillation of anterograde (PHA-L) tracers into the entorhinal cortes to map inputs to the hippocampus of control and kainate-treated rats. Cholinergic inputs will also be examined in the same manner to determine whether septal inputs to hippocampus are compromised in the epilepsy model. To test the hypothesis that surviving neurons in the CA3 subfield may sprout to re-establish their efferent systems following kainate-induced status, retrograde tracer will be injected into the perirhinal and entorhinal cortices. B. To extend ongoing investigations and precisely define any changes in the organization of glutamate receptor subunits (GluR 5/6/7, NR 1 & NR2 A/B) demonstrable by immunocytochemistry techniques using human hippocampal specimens removed at surgery for medically intractable temporal lobe epilepsy. As previously published for GluR1 & 2/3, the analyses will be correlated with several documented features of the reorganized sclerotic hippocampus and with age/gender-matched non-neuropathologic autopsy specimens. The pursuit of the proposed studies will allow the applicants to test the hypothesis that in the kainate model of TLE, hippocampal glutamatergic and cholinergic inputs are deafferented, and that alterations in glutamate receptor subunits become manifest in the hippocampus and contribute to the pathogenesis of certain types of epilepsy.
| Joseph, S A; Lynd-Balta, E; O'Banion, M K et al. (2006) Enhanced cyclooxygenase-2 expression in olfactory-limbic forebrain following kainate-induced seizures. Neuroscience 140:1051-65 |
| Rappold, P M; Lynd-Balta, E; Joseph, S A (2006) P2X7 receptor immunoreactive profile confined to resting and activated microglia in the epileptic brain. Brain Res 1089:171-8 |
