Hippocampal NPY gene transfer attenuates seizures without affecting epilepsy-induced impairment of LTP.
Recently, hippocampal neuropeptide Y (NPY) gene therapy has been shown to effectively suppress both acute and chronic seizures in animal model of epilepsy, thus representing a promising novel antiepileptic treatment strategy, particularly for patients with intractable mesial temporal lobe epilepsy (TLE). However, our previous studies show that recombinant adeno-associated viral (rAAV)-NPY treatment in naive rats attenuates long-term potentiation (LTP) and transiently impairs hippocampal learning process, indicating that negative effect on memory function could be a potential side effect of NPY gene therapy. Here we report how rAAV vector-mediated overexpression of NPY in the hippocampus affects rapid kindling, and subsequently explore how synaptic plasticity and transmission is affected by kindling and NPY overexpression by field recordings in CA1 stratum radiatum of brain slices. In animals injected with rAAV-NPY, we show that rapid kindling-induced hippocampal seizures in vivo are effectively suppressed as compared to rAAV-empty injected (control) rats. Six to nine weeks later, basal synaptic transmission and short-term synaptic plasticity are unchanged after rapid kindling, while LTP is significantly attenuated in vitro. Importantly, transgene NPY overexpression has no effect on short-term synaptic plasticity, and does not further compromise LTP in kindled animals. These data suggest that epileptic seizure-induced impairment of memory function in the hippocampus may not be further affected by rAAV-NPY treatment, and may be considered less critical for clinical application in epilepsy patients already experiencing memory disturbances.
Sørensen
Andreas T
AT
Experimental Epilepsy Group, Wallenberg Neuroscience Center, BMC A-11, Lund University Hospital, Lund, Sweden.
Nikitidou
Litsa
L
Ledri
Marco
M
Lin
En-Ju D
EJ
During
Matthew J
MJ
Kanter-Schlifke
Irene
I
Kokaia
Merab
M
D000704:Analysis of Variance; D000818:Animals; D055592:Biophysical Phenomena; D016009:Chi-Square Distribution; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000009:adverse effects; D004567:Electrodes, Implanted; D004569:Electroencephalography; D004827:Epilepsy / Q000209:etiology / Q000473:pathology* / Q000628:therapy*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods*; D006624:Hippocampus / Q000187:drug effects*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D009478:Neuropeptide Y / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014161:Transduction, Genetic
D009478:Neuropeptide Y