Mossy fiber sprouting and pyramidal cell dispersion in the hippocampal CA2 region in a mouse model of temporal lobe epilepsy.
Dentate granule cells and the hippocampal CA2 region are resistant to cell loss associated with mesial temporal lobe epilepsy (MTLE). It is known that granule cells undergo mossy fiber sprouting in the dentate gyrus which contributes to a recurrent, proepileptogenic circuitry in the hippocampus. Here it is shown that mossy fiber sprouting also targets CA2 pyramidal cell somata and that the CA2 region undergoes prominent structural reorganization under epileptic conditions. Using the intrahippocampal kainate mouse model for MTLE and the CA2-specific markers Purkinje cell protein 4 (PCP4) and regulator of G-Protein signaling 14 (RGS14), it was found that during epileptogenesis CA2 neurons survive and disperse in direction of CA3 and CA1 resulting in a significantly elongated CA2 region. Using transgenic mice that express enhanced green fluorescent protein (eGFP) in granule cells and mossy fibers, we show that the recently described mossy fiber projection to CA2 undergoes sprouting resulting in aberrant large, synaptoporin-expressing mossy fiber boutons which surround the CA2 pyramidal cell somata. This opens up the potential for altered synaptic transmission that might contribute to epileptic activity in CA2. Indeed, intrahippocampal recordings in freely moving mice revealed that epileptic activity occurs concomitantly in the dentate gyrus and in CA2. Altogether, the results call attention to CA2 as a region affected by MTLE-associated pathological restructuring.
Experimental Epilepsy Research, Department of Neurosurgery, University Medical Center Freiburg, Freiburg, 79106, Germany.
Ute
U
Häussler
Experimental Epilepsy Research, Department of Neurosurgery, University Medical Center Freiburg, Freiburg, 79106, Germany.
Katrin
K
Rinas
Faculty of Biology, University of Freiburg, Freiburg, 79104, Germany.|Bernstein Center Freiburg, University of Freiburg, Freiburg, 79104, Germany.|Laboratory for Biomicrotechnology, Department of Microsystems Engineering - IMTEK, Faculty of Engineering, University of Freiburg, Freiburg, 79110, Germany.
Antje
A
Kilias
Bernstein Center Freiburg, University of Freiburg, Freiburg, 79104, Germany.|Laboratory for Biomicrotechnology, Department of Microsystems Engineering - IMTEK, Faculty of Engineering, University of Freiburg, Freiburg, 79110, Germany.|BrainLinks-BrainTools, Cluster of Excellence, University of Freiburg, Freiburg, 79110, Germany.
Ulrich
U
Egert
Experimental Epilepsy Research, Department of Neurosurgery, University Medical Center Freiburg, Freiburg, 79106, Germany.|Bernstein Center Freiburg, University of Freiburg, Freiburg, 79104, Germany.|BrainLinks-BrainTools, Cluster of Excellence, University of Freiburg, Freiburg, 79110, Germany.
Carola A
CA
Haas
D000818:Animals; D056651:CA2 Region, Hippocampal / Q000473:pathology*; D004195:Disease Models, Animal; D004569:Electroencephalography; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000473:pathology*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005452:Fluoresceins / Q000493:pharmacokinetics; D007839:Functional Laterality; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019599:Mossy Fibers, Hippocampal / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology*; D020710:RGS Proteins / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D013997:Time Factors
D018690:Excitatory Amino Acid Agonists; D005452:Fluoresceins; D009419:Nerve Tissue Proteins; C489091:Pcp4 protein, mouse; D020710:RGS Proteins; C491399:Rgs14 protein, mouse; D016708:Synaptophysin; C504261:Synpr protein, mouse; C435731:fluoro jade; D049452:Green Fluorescent Proteins; D007608:Kainic Acid
Purkinje cell protein 4; dentate gyrus; epileptic activity; kainate; synapses