CA3 Synaptic Silencing Attenuates Kainic Acid-Induced Seizures and Hippocampal Network Oscillations.

Lily M Y Yu,Marie E Wintzer,Denis Polygalov,Thomas J Mchugh,Ming-Ching Chiang

doi:10.1523/eneuro.0003-16.2016

Lily M Y Yu, Marie E Wintzer + Show 3 more

Open Access

https://doi.org/10.1523/eneuro.0003-16.2016

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Journal: eNeuro	Publication Date: Jan 1, 2016
Citations: 52	License type: cc-by

Affiliation: RIKEN Center for Brain Science

Abstract

Epilepsy is a neurological disorder defined by the presence of seizure activity, manifest both behaviorally and as abnormal activity in neuronal networks. An established model to study the disorder in rodents is the systemic injection of kainic acid, an excitatory neurotoxin that at low doses quickly induces behavioral and electrophysiological seizures. Although the CA3 region of the hippocampus has been suggested to be crucial for kainic acid-induced seizure, because of its strong expression of kainate glutamate receptors and its high degree of recurrent connectivity, the precise role of excitatory transmission in CA3 in the generation of seizure and the accompanying increase in neuronal oscillations remains largely untested. Here we use transgenic mice in which CA3 pyramidal cell synaptic transmission can be inducibly silenced in the adult to demonstrate CA3 excitatory output is required for both the generation of epileptiform oscillatory activity and the progression of behavioral seizures.

Highlights

Temporal lobe epilepsy (TLE), a neurological disorder defined by the presences of severe seizures, remains a Received January 4, 2016; accepted February 1, 2016; First published February 11, 2016. 1The authors report no conflict of interest. 2Contributions: L.M.Y.Y. and T.J.M. designed research; L.M.Y.Y., M.E.W., and M.-C.C. performed research; L.M.Y.Y., D.P., and T.J.M. analyzed data; L.M.Y.Y., D.P., M.E.W., and T.J.M. wrote the paper.major clinical health issue worldwide
Having established that a loss of CA3 synaptic transmission severely attenuates the behavioral response to kainic acid (KA) injection, we addressed how the individual subfields of the hippocampus responded following drug administration
To examine neuronal activation we compared c-fos protein expression, a reliable indicator of neuronal activity (Labiner et al, 1993), across each of three hippocampal subfields in four groups of mice: CA3-tetanus toxin (TeTX) and control mice injected with KA or CA3-TeTX and control mice injected with saline

Summary

Introduction

Temporal lobe epilepsy (TLE), a neurological disorder defined by the presences of severe seizures, remains a Received January 4, 2016; accepted February 1, 2016; First published February 11, 2016. 1The authors report no conflict of interest. 2Contributions: L.M.Y.Y. and T.J.M. designed research; L.M.Y.Y., M.E.W., and M.-C.C. performed research; L.M.Y.Y., D.P., and T.J.M. analyzed data; L.M.Y.Y., D.P., M.E.W., and T.J.M. wrote the paper.major clinical health issue worldwide. Animal models of TLE have been extremely useful in identifying the basic cellular mechanisms of epileptogenesis and have provided an assay system to test the effectiveness of interventions that may halt the onset or progression of seizures (Ben-Ari and Cossart, 2000; Leite et al, 2002). A useful protocol employs the excitatory neurotoxin kainic acid (KA) to induce both acute seizures and in January/February 2016, 3(1) e0003-16.2016 1–18 a subset of animals, progression to status epilepticus (Ben-Ari, 1985). It has been suggested that KA leads to excitation of both excitatory and inhibitory neurons with the balance tipping towards excitation and seizure generation, direct tests of this model have been lacking (Ben-Ari and Cossart, 2000)

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