title: Increased sensitivity to kindling in mice lacking TSP1.
abstract: The development of a hyperexcitable neuronal network is thought to be a critical event in epilepsy. Thrombospondins (TSPs) regulate synaptogenesis by binding the neuronal α2δ subunit of the voltage-gated calcium channel. TSPs regulate synapse formation during development and in the mature brain following injury. It is unclear if TSPs are involved in hyperexcitability that contributes to the development of epilepsy. Here we explore the development of epilepsy using a pentylenetetrazole (PTZ) kindling model in mice lacking TSP1 and TSP2. Unexpectedly, we found increased sensitivity to PTZ kindling in mice lacking TSP1, while mice lacking TSP2 kindled similar to wild-type. We found that the increased seizure susceptibility in the TSP1 knockout (KO) mice was not due to a compensatory increase in TSP2 mRNA as TSP1/2 KO mice were sensitive to PTZ, similar to the TSP1 KO mice. Furthermore, there were similar levels of TGF-B signal activation during kindling in the TSP1 KO mice compared to wild-type. We observed decreased expression of voltage-dependent calcium channel subunit CACNA2D1 mRNA in TSP1, TSP2, and TSP1/2 KO mice. Decreased CACNA2D2 mRNA was only detected in mice that lacked TSP1 and α2δ-1/2 protein levels in the cortex were lower in the TSP 1/2 KO mice. CACNA2D2 knockout mice have spontaneous seizures and increased PTZ seizure susceptibility. Here we report similar findings, TSP1, and TSP1/2 KO mice have low levels of CACNA2D2 mRNA expression and α2δ-1/2 receptor level in the cortex, and are more susceptible to seizures. CACNA2D2 mutations in mice and humans can cause epilepsy. Our data suggest TSP1 in particular may control CACNA2D2 levels and could be a modifier of seizure susceptibility.
authors.affiliation: The Department of Neurology, School of Medicine, Stanford University, Stanford, CA 94305, USA; The Department of Otolaryngology - Head and Neck Surgery, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: D
authors.initials: D
authors.lastname: Mendus
authors.affiliation: The Department of Neurology, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: E K
authors.initials: EK
authors.lastname: Rankin-Gee
authors.affiliation: The Department of Otolaryngology - Head and Neck Surgery, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: M
authors.initials: M
authors.lastname: Mustapha
authors.affiliation: The Department of Neurology, School of Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: brenda2@stanford.edu.
authors.forename: B E
authors.initials: BE
authors.lastname: Porter
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D004195:Disease Models, Animal; D007696:Kindling, Neurologic / Q000187:drug effects* / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010433:Pentylenetetrazole / Q000009:adverse effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012640:Seizures / Q000209:etiology / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects; D019700:Thrombospondin 1 / Q000172:deficiency* / Q000235:genetics; D019699:Thrombospondins / Q000172:deficiency / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000099262:Thrombospondin 2
chemical_list: D015220:Calcium Channels; D010433:Pentylenetetrazole; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D019700:Thrombospondin 1; D019699:Thrombospondins; D000099262:Thrombospondin 2; C512066:CACNA2D1 protein, mouse; C486058:Cacna2d2 protein, mouse; C585483:Thbs1 protein, mouse
keywords: epileptogenesis; gene expression; ictogenesis; mouse model; seizure; voltage-gated calcium channel