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(Abst. 3.355), 2009

Authors: Sloka Iyengar and D. Mott
Content: Rationale: Temporal lobe epilepsy (TLE) caused by status epilepticus (SE) or brain injury can be associated with cognitive decline. These detrimental changes in learning and memory may be due to alterations in induction or expression of long term potentiation (LTP). Neuregulin (NRG) is a peptide that is released from hippocampal synapses in an activity dependent manner and acts on ErbB4 tyrosine kinase receptors to limit LTP. We investigated changes in NRG/ErbB4 regulation of LTP in epilepsy. Methods: Adult male Sprague Dawley rats were treated with the chemoconvulsant pilocarpine in order to induce SE and eventually, TLE. A separate group of rats were treated with saline instead of pilocarpine and were used as sham-controls. Brain slice electrophysiology was done on rats 25 days after treatment to study changes in LTP caused by epilepsy. Results: We found that activation of ErbB4 receptors by NRG had opposing effects on LTP in slices from sham-treated and SE-experienced rats. Application of NRG blocked LTP in sham-treated slices, while enhancing LTP 25 days post-SE. In line with these results, we found that the ErbB4 antagonist PD-158,780 significantly enhanced LTP in sham-treated slices, whereas it blocked LTP 25 days post-SE. The facilitatory action of NRG on LTP during epilepsy was mediated through ErbB4 receptors as AG 1478; an ErbB4 antagonist abolished the actions of applied NRG. In addition to facilitating LTP in slices from epileptic rats, NRG also enhanced LTP induction by enabling a sub-threshold stimulus train to produce LTP, suggesting that NRG/ErbB4 signaling is required for LTP during epilepsy. The mechanism behind this shift in NRG/ErbB4 function in epilepsy is unknown. NRG inhibits LTP by facilitating the release of dopamine (DA) which acts on D4-type DA receptors. Activation of D4-like DA receptors inhibits LTP, whereas activation of D1/D5-type DA receptors enhances LTP. We used selective D1/D5 as well as D4 antagonists to observe whether a change in DA receptor function could explain the switch in NRG action. We found that as expected, co-application of the D4 antagonist L-745,870 with NRG in sham-treated slices prevented the effects of NRG. In slices from the same (sham) animals, a D1/D5 antagonist SCH 39166 did not prevent the effects of applied NRG. In contrast, in slices from SE-experienced rats, L-745,870 did not alter the effects of NRG on LTP whereas SCH 39166 completely blocked the effects of NRG on LTP. These results suggest that in sham treated slices, NRG causes activation of D4-like DA receptors to block LTP, whereas in epilepsy, NRG causes activation of D1/D5-like DA receptors to facilitate LTP. Conclusions: Our results indicate that NRG inhibits LTP in control conditions, but is required for LTP in epilepsy. This switch in NRG action is necessary to maintain epilepsy in the epileptic state and can be explained by an underlying change in regulation of LTP by differential DA receptor subtypes.