PMID- 28823934 OWN - NLM STAT- MEDLINE DCOM- 20180723 LR - 20201021 IS - 1095-953X (Electronic) IS - 0969-9961 (Print) IS - 0969-9961 (Linking) VI - 108 DP - 2017 Dec TI - Structural alterations in fast-spiking GABAergic interneurons in a model of posttraumatic neocortical epileptogenesis. PG - 100-114 LID - S0969-9961(17)30189-4 [pii] LID - 10.1016/j.nbd.2017.08.008 [doi] AB - Electrophysiological experiments in the partial cortical isolation ("undercut" or "UC") model of injury-induced neocortical epileptogenesis have shown alterations in GABAergic synaptic transmission attributable to abnormalities in presynaptic terminals. To determine whether the decreased inhibition was associated with structural abnormalities in GABAergic interneurons, we used immunocytochemical techniques, confocal microscopy and EM in UC and control sensorimotor rat cortex to analyze structural alterations in fast-spiking parvalbumin-containing interneurons and pyramidal (Pyr) cells of layer V. Principle findings were: 1) there were no decreases in counts of parvalbumin (PV)- or GABA-immunoreactive interneurons in UC cortex, however there were significant reductions in expression of VGAT and GAD-65 and -67 in halos of GABAergic terminals around Pyr somata in layer V. 2) Consistent with previous results, somatic size and density of Pyr cells was decreased in infragranular layers of UC cortex. 3) Dendrites of biocytin-filled FS interneurons were significantly decreased in volume. 4) There were decreases in the size and VGAT content of GABAergic boutons in axons of biocytin-filled FS cells in the UC, together with a decrease in colocalization with postsynaptic gephyrin, suggesting a reduction in GABAergic synapses. Quantitative EM of layer V Pyr somata confirmed the reduction in inhibitory synapses. 5) There were marked and lasting reductions in brain derived neurotrophic factor (BDNF)-IR and -mRNA in Pyr cells and decreased TrkB-IR on PV cells in UC cortex. 6) Results lead to the hypothesis that reduction in trophic support by BDNF derived from Pyr cells may contribute to the regressive changes in axonal terminals and dendrites of FS cells in the UC cortex and decreased GABAergic inhibition. SIGNIFICANCE: Injury to cortical structures is a major cause of epilepsy, accounting for about 20% of cases in the general population, with an incidence as high as ~50% among brain-injured personnel in wartime. Loss of GABAergic inhibitory interneurons is a significant pathophysiological factor associated with epileptogenesis following brain trauma and other etiologies. Results of these experiments show that the largest population of cortical interneurons, the parvalbumin-containing fast-spiking (FS) interneurons, are preserved in the partial neocortical isolation model of partial epilepsy. However, axonal terminals of these cells are structurally abnormal, have decreased content of GABA synthetic enzymes and vesicular GABA transporter and make fewer synapses onto pyramidal neurons. These structural abnormalities underlie defects in GABAergic neurotransmission that are a key pathophysiological factor in epileptogenesis found in electrophysiological experiments. BDNF, and its TrkB receptor, key factors for maintenance of interneurons and pyramidal neurons, are decreased in the injured cortex. Results suggest that supplying BDNF to the injured epileptogenic brain may reverse the structural and functional abnormalities in the parvalbumin FS interneurons and provide an antiepileptogenic therapy. CI - Copyright (c) 2017 Elsevier Inc. All rights reserved. FAU - Gu, Feng AU - Gu F AD - Epilepsy Research Laboratories, Stanford Univ. Sch. of Medicine, United States. FAU - Parada, Isabel AU - Parada I AD - Epilepsy Research Laboratories, Stanford Univ. Sch. of Medicine, United States. FAU - Shen, Fran AU - Shen F AD - Epilepsy Research Laboratories, Stanford Univ. Sch. of Medicine, United States. FAU - Li, Judith AU - Li J AD - Epilepsy Research Laboratories, Stanford Univ. Sch. of Medicine, United States. FAU - Bacci, Alberto AU - Bacci A AD - ICM - Hopital Pitie Salpetriere, 7, bd de l'hopital, 75013 Paris, France. FAU - Graber, Kevin AU - Graber K AD - Epilepsy Research Laboratories, Stanford Univ. Sch. of Medicine, United States. FAU - Taghavi, Reza Moein AU - Taghavi RM AD - Epilepsy Research Laboratories, Stanford Univ. Sch. of Medicine, United States. FAU - Scalise, Karina AU - Scalise K AD - Epilepsy Research Laboratories, Stanford Univ. Sch. of Medicine, United States. FAU - Schwartzkroin, Philip AU - Schwartzkroin P AD - Department of Neurological Surgery, University of California, Davis, United States. FAU - Wenzel, Jurgen AU - Wenzel J AD - Department of Neurological Surgery, University of California, Davis, United States. FAU - Prince, David A AU - Prince DA AD - Epilepsy Research Laboratories, Stanford Univ. Sch. of Medicine, United States. Electronic address: daprince@stanford.edu. LA - eng GR - R01 NS039579/NS/NINDS NIH HHS/United States GR - P01 NS012151/NS/NINDS NIH HHS/United States GR - P50 NS012151/NS/NINDS NIH HHS/United States GR - R01 NS006477/NS/NINDS NIH HHS/United States GR - R56 NS039579/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20170818 PL - United States TA - Neurobiol Dis JT - Neurobiology of disease JID - 9500169 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Parvalbumins) RN - 0 (RNA, Messenger) RN - 0 (Slc32a1 protein, rat) RN - 0 (Synaptophysin) RN - 0 (Vesicular Inhibitory Amino Acid Transport Proteins) RN - EC 2.7.10.1 (Ntrk2 protein, rat) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 4.1.1.15 (Glutamate Decarboxylase) RN - EC 4.1.1.15 (glutamate decarboxylase 1) SB - IM MH - Action Potentials MH - Animals MH - Brain-Derived Neurotrophic Factor/metabolism MH - Disease Models, Animal MH - Epilepsy, Post-Traumatic/*pathology/physiopathology MH - GABAergic Neurons/*pathology/physiology MH - Glutamate Decarboxylase/metabolism MH - Immunohistochemistry MH - Interneurons/*pathology/physiology MH - Male MH - Microscopy, Confocal MH - Microscopy, Electron MH - Neocortex/pathology/physiopathology MH - Parvalbumins/metabolism MH - Pyramidal Cells/pathology/physiology MH - RNA, Messenger/metabolism MH - Rats, Sprague-Dawley MH - Receptor, trkB/metabolism MH - Synaptophysin/metabolism MH - Vesicular Inhibitory Amino Acid Transport Proteins/metabolism PMC - PMC5927780 MID - NIHMS902327 OTO - NOTNLM OT - Axonal boutons OT - BDNF OT - Epilepsy OT - GABA OT - Inhibitory synapses OT - Parvalbumin OT - Traumatic injury OT - TrkB OT - Trophic EDAT- 2017/08/22 06:00 MHDA- 2018/07/24 06:00 PMCR- 2018/12/01 CRDT- 2017/08/22 06:00 PHST- 2017/04/06 00:00 [received] PHST- 2017/08/11 00:00 [revised] PHST- 2017/08/16 00:00 [accepted] PHST- 2017/08/22 06:00 [pubmed] PHST- 2018/07/24 06:00 [medline] PHST- 2017/08/22 06:00 [entrez] PHST- 2018/12/01 00:00 [pmc-release] AID - S0969-9961(17)30189-4 [pii] AID - 10.1016/j.nbd.2017.08.008 [doi] PST - ppublish SO - Neurobiol Dis. 2017 Dec;108:100-114. doi: 10.1016/j.nbd.2017.08.008. Epub 2017 Aug 18.