Galanin gene transfer curtails generalized seizures in kindled rats without altering hippocampal synaptic plasticity

TY - JOUR

T1 - Galanin gene transfer curtails generalized seizures in kindled rats without altering hippocampal synaptic plasticity

AU - Kanter-Schlifke, I

AU - Toft Sørensen, Andreas

AU - Ledri, M

AU - Kuteeva, E

AU - Hökfelt, T

AU - Kokaia, M

PY - 2007/12/19

Y1 - 2007/12/19

N2 - Gene therapy-based overexpression of endogenous seizure-suppressing molecules represents a promising treatment strategy for epilepsy. Viral vector-based overexpression of the neuropeptide galanin has been shown to effectively suppress generalized seizures in various animal models of epilepsy. However, it has not been explored whether such treatment can also prevent the epileptogenesis. Using a recombinant adeno-associated viral (rAAV) vector, we induced hippocampal galanin overexpression under the neuron specific enolase promoter in rats. Here we report that in animals with galanin overexpression, the duration of electrographic afterdischarges was shortened and initiation of convulsions was delayed at generalized seizure stages. However, the hippocampal kindling development was unchanged. Short-term plasticity of mossy fiber-cornu ammonis (CA) 3 synapses was unaltered, as assessed by paired-pulse and frequency facilitation of field excitatory postsynaptic potentials (fEPSPs) in hippocampal slices, suggesting that despite high transgene galanin expression, overall release probability of glutamate in these synapses was unaffected. These data indicate that hippocampal rAAV-based galanin overexpression is capable of mediating anticonvulsant effects by lowering the seizure susceptibility once generalized seizures are induced, but does not seem to affect kindling development or presynaptic short-term plasticity in mossy fibers.

AB - Gene therapy-based overexpression of endogenous seizure-suppressing molecules represents a promising treatment strategy for epilepsy. Viral vector-based overexpression of the neuropeptide galanin has been shown to effectively suppress generalized seizures in various animal models of epilepsy. However, it has not been explored whether such treatment can also prevent the epileptogenesis. Using a recombinant adeno-associated viral (rAAV) vector, we induced hippocampal galanin overexpression under the neuron specific enolase promoter in rats. Here we report that in animals with galanin overexpression, the duration of electrographic afterdischarges was shortened and initiation of convulsions was delayed at generalized seizure stages. However, the hippocampal kindling development was unchanged. Short-term plasticity of mossy fiber-cornu ammonis (CA) 3 synapses was unaltered, as assessed by paired-pulse and frequency facilitation of field excitatory postsynaptic potentials (fEPSPs) in hippocampal slices, suggesting that despite high transgene galanin expression, overall release probability of glutamate in these synapses was unaffected. These data indicate that hippocampal rAAV-based galanin overexpression is capable of mediating anticonvulsant effects by lowering the seizure susceptibility once generalized seizures are induced, but does not seem to affect kindling development or presynaptic short-term plasticity in mossy fibers.

KW - Animals

KW - Dependovirus

KW - Disease Models, Animal

KW - Dose-Response Relationship, Radiation

KW - Electric Stimulation

KW - Excitatory Postsynaptic Potentials

KW - Galanin

KW - Gene Transfer Techniques

KW - Genetic Vectors

KW - Hippocampus

KW - Kindling, Neurologic

KW - Male

KW - Neuronal Plasticity

KW - Rats

KW - Rats, Sprague-Dawley

KW - Reaction Time

KW - Seizures

KW - Time Factors

KW - Journal Article

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

U2 - 10.1016/j.neuroscience.2007.09.056

DO - 10.1016/j.neuroscience.2007.09.056

M3 - Journal article

C2 - 17988802

SN - 0306-4522

VL - 150

SP - 984

EP - 992

JO - Neuroscience

JF - Neuroscience

IS - 4

ER -