Neuregulin blocks synaptic strengthening after epileptiform activity in the rat hippocampus.
Synaptic strengthening produced by epileptiform activity may contribute to seizure progression and cognitive impairment in epilepsy. Agents that limit this form of plasticity may have therapeutic benefit. Neuregulin is an endogenous growth factor that is released at synapses in an activity dependent manner and can suppress long term potentiation (LTP). Alterations in neuregulin signaling have been associated with schizophrenia. A role for neuregulin in epilepsy has not been explored. We used field potential recordings to examine the role of neuregulin in regulating synaptic strengthening following epileptiform activity in hippocampal slices. Neuregulin had no effect on basal synaptic transmission, isolated NMDA field potentials or GABAergic inhibition on CA1 pyramidal neurons. However, it reversed LTP at CA1 synapses. Brief exposure to 10 mM potassium chloride produced epileptiform bursting and potentiation of CA1 synapses and suppressed the subsequent induction of LTP. Neuregulin reversed high K(+)-induced synaptic strengthening, enabling LTP induction after neuregulin washout. In this manner neuregulin preserved the dynamic range of synaptic responses and plasticity after epileptiform activity. These results indicate that LTP and high K(+)-induced synaptic strengthening share a common neuregulin-sensitive mechanism. By opposing synaptic strengthening caused by epileptiform activity, we suggest that neuregulin may reduce the generation and spread of seizures as well as memory deficits associated with epilepsy.
Iyengar
Sloka S
SS
Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
Mott
David D
DD
D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000031:analogs & derivatives / Q000494:pharmacology; D004827:Epilepsy / Q000503:physiopathology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D020880:Neuregulins / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
D018690:Excitatory Amino Acid Agonists; D020880:Neuregulins; C017069:bicuculline methiodide; D016202:N-Methylaspartate; D011188:Potassium; D001640:Bicuculline