title: Neonatal seizures induced by pentylenetetrazol or kainic acid disrupt primary cilia growth on developing mouse cortical neurons.
abstract: Neonatal or early-life seizures (ELS) are often associated with life-long neurophysiological, cognitive and behavioral deficits, but the underlying mechanisms contributing to these deficits remain poorly understood. Newborn, post-migratory cortical neurons sprout ciliary buds (procilia) that mature into primary cilia. Disruption of the growth or signaling capabilities of these cilia has been linked to atypical neurite outgrowth from neurons and abnormalities in neuronal circuitry. Here, we tested the hypothesis that generalized seizures induced by pentylenetetrazol (PTZ) or kainic acid (KA) during early postnatal development impair neuronal and/or glial ciliogenesis. Mice received PTZ (50 or 100mg/kg), KA (2mg/kg), or saline either once at birth (P0), or once daily from P0 to P4. Using immunohistochemistry and electron microscopy, the cilia of neurons and glia were examined at P7, P14, and P42. A total of 83 regions were analyzed, representing 13 unique neocortical and hippocampal regions. Neuronal cilia were identified by co-expression of NeuN and type 3 adenylyl cyclase (ACIII) or somatostatin receptor 3 (SSTR3), while glial cilia were identified by co-expression of GFAP, Arl13b, and gamma-tubulin. We found that PTZ exposure at either P0 or from P0 to P4 induced convulsive behavior, followed by acute and lasting effects on neuronal cilia lengths that varied depending on the cortical region, PTZ dose, injection frequency, and time post-PTZ. Both increases and decreases in neuronal cilia length were observed. No changes in the length of glial cilia were observed under any of the test conditions. Lastly, we found that a single KA seizure at P0 led to similar abnormalities in neuronal cilia lengths. Our results suggest that seizure(s) occurring during early stages of cortical development induce persistent and widespread changes in neuronal cilia length. Given the impact neuronal cilia have on neuronal differentiation, ELS-induced changes in ciliogenesis may contribute to long-term pathology and abnormal cortical function.
authors.affiliation: Department of Neuroscience, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Alexander K
authors.initials: AK
authors.lastname: Parker
authors.affiliation: Department of Neuroscience, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Le
authors.affiliation: Department of Neuroscience, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Tyler S
authors.initials: TS
authors.lastname: Smith
authors.affiliation: Department of Neuroscience, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Lan B
authors.initials: LB
authors.lastname: Hoang-Minh
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, Florida 32610, United States; Child Health Research Institute, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Atkinson
authors.affiliation: Department of Neuroscience, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: George
authors.initials: G
authors.lastname: Ugartemendia
authors.affiliation: Department of Neuroscience, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Semple-Rowland
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, Florida 32610, United States; Child Health Research Institute, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Coleman
authors.affiliation: Department of Neuroscience, University of Florida, Gainesville, Florida 32610, United States. Electronic address: msarkisian@ufl.edu.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Sarkisian
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D003292:Convulsants / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007608:Kainic Acid / Q000633:toxicity*; D051379:Mice; D016253:Microscopy, Immunoelectron; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D010433:Pentylenetetrazole / Q000633:toxicity*; D012640:Seizures / Q000139:chemically induced* / Q000473:pathology
chemical_list: D003292:Convulsants; D009419:Nerve Tissue Proteins; D007608:Kainic Acid; D010433:Pentylenetetrazole
keywords: Ciliogenesis; Cilium; Epilepsy; Immature brain; Neonate