Hippocampal NPY gene transfer attenuates seizures without affecting epilepsy-induced impairment of LTP

TY - JOUR

T1 - Hippocampal NPY gene transfer attenuates seizures without affecting epilepsy-induced impairment of LTP

AU - Sørensen, Andreas T

AU - Nikitidou, Litsa

AU - Ledri, Marco

AU - Lin, En-Ju D

AU - During, Matthew J

AU - Kanter-Schlifke, Irene

AU - Kokaia, Merab

PY - 2009/2

Y1 - 2009/2

N2 - 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.

AB - 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.

KW - Analysis of Variance

KW - Animals

KW - Biophysical Phenomena

KW - Chi-Square Distribution

KW - Disease Models, Animal

KW - Electric Stimulation

KW - Electrodes, Implanted

KW - Electroencephalography

KW - Epilepsy

KW - Excitatory Postsynaptic Potentials

KW - Genetic Therapy

KW - Hippocampus

KW - Long-Term Potentiation

KW - Male

KW - Neuropeptide Y

KW - Rats

KW - Rats, Sprague-Dawley

KW - Transduction, Genetic

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.expneurol.2008.10.015

DO - 10.1016/j.expneurol.2008.10.015

M3 - Journal article

C2 - 19038255

SN - 0014-4886

VL - 215

SP - 328

EP - 333

JO - Experimental Neurology

JF - Experimental Neurology

IS - 2

ER -