NPY gene transfer in the hippocampus attenuates synaptic plasticity and learning

TY - JOUR

T1 - NPY gene transfer in the hippocampus attenuates synaptic plasticity and learning

AU - Sørensen, Andreas T

AU - Kanter-Schlifke, Irene

AU - Carli, Mirjana

AU - Balducci, Claudia

AU - Noe, Francesco

AU - During, Matthew J

AU - Vezzani, Annamaria

AU - Kokaia, Merab

N1 - (c) 2008 Wiley-Liss, Inc.

PY - 2008

Y1 - 2008

N2 - Recombinant adeno-associated viral (rAAV) vector-induced neuropeptide Y (NPY) overexpression in the hippocampus exerts powerful antiepileptic and antiepileptogenic effects in rats. Such gene therapy approach could be a valuable alternative for developing new antiepileptic treatment strategies. Future clinical progress, however, requires more detailed evaluation of possible side effects of this treatment. Until now it has been unknown whether rAAV vector-based NPY overexpression in the hippocampus alters normal synaptic transmission and plasticity, which could disturb learning and memory processing. Here we show, by electrophysiological recordings in CA1 of the hippocampal formation of rats, that hippocampal NPY gene transfer into the intact brain does not affect basal synaptic transmission, but slightly alters short-term synaptic plasticity, most likely via NPY Y2 receptor-mediated mechanisms. In addition, transgene NPY seems to be released during high frequency neuronal activity, leading to decreased glutamate release in excitatory synapses. Importantly, memory consolidation appears to be affected by the treatment. We found that long-term potentiation (LTP) in the CA1 area is partially impaired and animals have a slower rate of hippocampal-based spatial discrimination learning. These data provide the first evidence that rAAV-based gene therapy using NPY exerts relative limited effect on synaptic plasticity and learning in the hippocampus, and therefore this approach could be considered as a viable alternative for epilepsy treatment.

AB - Recombinant adeno-associated viral (rAAV) vector-induced neuropeptide Y (NPY) overexpression in the hippocampus exerts powerful antiepileptic and antiepileptogenic effects in rats. Such gene therapy approach could be a valuable alternative for developing new antiepileptic treatment strategies. Future clinical progress, however, requires more detailed evaluation of possible side effects of this treatment. Until now it has been unknown whether rAAV vector-based NPY overexpression in the hippocampus alters normal synaptic transmission and plasticity, which could disturb learning and memory processing. Here we show, by electrophysiological recordings in CA1 of the hippocampal formation of rats, that hippocampal NPY gene transfer into the intact brain does not affect basal synaptic transmission, but slightly alters short-term synaptic plasticity, most likely via NPY Y2 receptor-mediated mechanisms. In addition, transgene NPY seems to be released during high frequency neuronal activity, leading to decreased glutamate release in excitatory synapses. Importantly, memory consolidation appears to be affected by the treatment. We found that long-term potentiation (LTP) in the CA1 area is partially impaired and animals have a slower rate of hippocampal-based spatial discrimination learning. These data provide the first evidence that rAAV-based gene therapy using NPY exerts relative limited effect on synaptic plasticity and learning in the hippocampus, and therefore this approach could be considered as a viable alternative for epilepsy treatment.

KW - Animals

KW - Arginine

KW - Benzazepines

KW - Dependovirus

KW - Discrimination (Psychology)

KW - Excitatory Postsynaptic Potentials

KW - Genetic Therapy

KW - Genetic Vectors

KW - Hippocampus

KW - Injections

KW - Long-Term Potentiation

KW - Male

KW - Memory Disorders

KW - Neuronal Plasticity

KW - Neuropeptide Y

KW - Rats

KW - Rats, Sprague-Dawley

KW - Receptors, Neuropeptide Y

KW - Recombinant Fusion Proteins

KW - Transduction, Genetic

KW - Transgenes

KW - Journal Article

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

U2 - 10.1002/hipo.20415

DO - 10.1002/hipo.20415

M3 - Journal article

C2 - 18306304

SN - 1050-9631

VL - 18

SP - 564

EP - 574

JO - Hippocampus

JF - Hippocampus

IS - 6

ER -