Locally Reducing KCC2 Activity in the Hippocampus is Sufficient to Induce Temporal Lobe Epilepsy
Matt R. Kelley,
Ross A. Cardarelli,
Joshua L. Smalley,
Thomas A. Ollerhead,
Peter M. Andrew,
Nicholas J. Brandon,
Tarek Z. Deeb,
Stephen J. Moss
Affiliations
Matt R. Kelley
Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA
Ross A. Cardarelli
AstraZeneca-Tufts University Laboratory for Basic and Translational Neuroscience Research, Boston, MA, USA
Joshua L. Smalley
Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA
Thomas A. Ollerhead
Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA
Peter M. Andrew
Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA
Nicholas J. Brandon
AstraZeneca-Tufts University Laboratory for Basic and Translational Neuroscience Research, Boston, MA, USA; Neuroscience, IMED Biotech Unit, AstraZeneca, Boston, MA, USA
Tarek Z. Deeb
Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA; AstraZeneca-Tufts University Laboratory for Basic and Translational Neuroscience Research, Boston, MA, USA
Stephen J. Moss
Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA; AstraZeneca-Tufts University Laboratory for Basic and Translational Neuroscience Research, Boston, MA, USA; Neuroscience, IMED Biotech Unit, AstraZeneca, Boston, MA, USA; Department of Neuroscience, Physiology and Pharmacology, University College, London, WC1E, 6BT, UK; Corresponding author at: Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA.
Mesial temporal lobe epilepsy (mTLE) is the most common form of epilepsy, believed to arise in part from compromised GABAergic inhibition. The neuronal specific K+/Cl− co-transporter 2 (KCC2) is a critical determinant of the efficacy of GABAergic inhibition and deficits in its activity are observed in mTLE patients and animal models of epilepsy. To test if reductions of KCC2 activity directly contribute to the pathophysiology of mTLE, we locally ablated KCC2 expression in a subset of principal neurons within the adult hippocampus. Deletion of KCC2 resulted in compromised GABAergic inhibition and the development of spontaneous, recurrent generalized seizures. Moreover, local ablation of KCC2 activity resulted in hippocampal sclerosis, a key pathological change seen in mTLE. Collectively, our results demonstrate that local deficits in KCC2 activity within the hippocampus are sufficient to precipitate mTLE. Keywords: KCC2, GABA, Epilepsy, Hippocampal sclerosis
