title: Alterations in Brain Inflammation, Synaptic Proteins, and Adult Hippocampal Neurogenesis during Epileptogenesis in Mice Lacking Synapsin2.
abstract: Synapsins are pre-synaptic vesicle-associated proteins linked to the pathogenesis of epilepsy through genetic association studies in humans. Deletion of synapsins causes an excitatory/inhibitory imbalance, exemplified by the epileptic phenotype of synapsin knockout mice. These mice develop handling-induced tonic-clonic seizures starting at the age of about 3 months. Hence, they provide an opportunity to study epileptogenic alterations in a temporally controlled manner. Here, we evaluated brain inflammation, synaptic protein expression, and adult hippocampal neurogenesis in the epileptogenic (1 and 2 months of age) and tonic-clonic (3.5-4 months) phase of synapsin 2 knockout mice using immunohistochemical and biochemical assays. In the epileptogenic phase, region-specific microglial activation was evident, accompanied by an increase in the chemokine receptor CX3CR1, interleukin-6, and tumor necrosis factor-α, and a decrease in chemokine keratinocyte chemoattractant/ growth-related oncogene. Both post-synaptic density-95 and gephyrin, scaffolding proteins at excitatory and inhibitory synapses, respectively, showed a significant up-regulation primarily in the cortex. Furthermore, we observed an increase in the inhibitory adhesion molecules neuroligin-2 and neurofascin and potassium chloride co-transporter KCC2. Decreased expression of γ-aminobutyric acid receptor-δ subunit and cholecystokinin was also evident. Surprisingly, hippocampal neurogenesis was reduced in the epileptogenic phase. Taken together, we report molecular alterations in brain inflammation and excitatory/inhibitory balance that could serve as potential targets for therapeutics and diagnostic biomarkers. In addition, the regional differences in brain inflammation and synaptic protein expression indicate an epileptogenic zone from where the generalized seizures in synapsin 2 knockout mice may be initiated or spread.
authors.affiliation: Inflammation and Stem Cell Therapy Group, Division of Clinical Neurophysiology, Lund University, SE-221 84, Lund, Sweden; Lund Epilepsy Center, Lund University, SE-221 84, Lund, Sweden.
authors.forename: Deepti
authors.initials: D
authors.lastname: Chugh
authors.affiliation: Inflammation and Stem Cell Therapy Group, Division of Clinical Neurophysiology, Lund University, SE-221 84, Lund, Sweden; Lund Epilepsy Center, Lund University, SE-221 84, Lund, Sweden.
authors.forename: Idrish
authors.initials: I
authors.lastname: Ali
authors.affiliation: Inflammation and Stem Cell Therapy Group, Division of Clinical Neurophysiology, Lund University, SE-221 84, Lund, Sweden; Lund Epilepsy Center, Lund University, SE-221 84, Lund, Sweden.
authors.forename: Anahita
authors.initials: A
authors.lastname: Bakochi
authors.affiliation: Institute of Basic Medical Sciences, Department of Physiology, University of Oslo, Oslo, Norway.
authors.forename: Elma
authors.initials: E
authors.lastname: Bahonjic
authors.affiliation: Institute of Basic Medical Sciences, Department of Physiology, University of Oslo, Oslo, Norway; Section of Clinical Neurophysiology, Department of Neurology, Oslo University Hospital, Oslo, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Etholm
authors.affiliation: Inflammation and Stem Cell Therapy Group, Division of Clinical Neurophysiology, Lund University, SE-221 84, Lund, Sweden; Lund Epilepsy Center, Lund University, SE-221 84, Lund, Sweden.
authors.forename: Christine T
authors.initials: CT
authors.lastname: Ekdahl
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D004660:Encephalitis / Q000378:metabolism / Q000473:pathology*; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis; D012640:Seizures / Q000378:metabolism / Q000473:pathology*; D013569:Synapses / Q000378:metabolism*; D016704:Synapsins / Q000172:deficiency / Q000235:genetics*; D015854:Up-Regulation; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; D018925:Chemokines; D016207:Cytokines; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D016704:Synapsins; C073441:gephyrin; C093438:neuroligin 1; C098003:neuroligin 2; D005680:gamma-Aminobutyric Acid; D051528:Guanylate Kinases