title: Decreased number of interneurons and increased seizures in neuropilin 2 deficient mice: implications for autism and epilepsy.
abstract: OBJECTIVE
  Clinically, perturbations in the semaphorin signaling system have been associated with autism and epilepsy. The semaphorins have been implicated in guidance, migration, differentiation, and synaptic plasticity of neurons. The semaphorin 3F (Sema3F) ligand and its receptor, neuropilin 2 (NPN2) are highly expressed within limbic areas. NPN2 signaling may intimately direct the apposition of presynaptic and postsynaptic locations, facilitating the development and maturity of hippocampal synaptic function. To further understand the role of NPN2 signaling in central nevous system (CNS) plasticity, structural and functional alterations were assessed in NPN2 deficient mice.
  
  
  METHODS
  In NPN2 deficient mice, we measured seizure susceptibility after kainic acid or pentylenetetrazol, neuronal excitability and synaptic throughput in slice preparations, principal and interneuron cell counts with immunocytochemical protocols, synaptosomal protein levels with immunoblots, and dendritic morphology with Golgi-staining.
  
  
  RESULTS
  NPN2 deficient mice had shorter seizure latencies, increased vulnerability to seizure-related death, were more likely to develop spontaneous recurrent seizure activity after chemical challenge, and had an increased slope on input/output curves. Principal cell counts were unchanged, but GABA, parvalbumin, and neuropeptide Y interneuron cell counts were significantly reduced. Synaptosomal NPN2 protein levels and total number of GABAergic synapses were decreased in a gene dose-dependent fashion. CA1 pyramidal cells showed reduced dendritic length and complexity, as well as an increased number of dendritic spines.
  
  
  CONCLUSIONS
  These data suggest the novel hypothesis that the Sema 3F signaling system's role in appropriate placement of subsets of hippocampal interneurons has critical downstream consequences for hippocampal function, resulting in a more seizure susceptible phenotype.
authors.affiliation: Departments of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Gant
authors.forename: Oliver
authors.initials: O
authors.lastname: Thibault
authors.forename: Eric M
authors.initials: EM
authors.lastname: Blalock
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Adam
authors.initials: A
authors.lastname: Bachstetter
authors.forename: James
authors.initials: J
authors.lastname: Kotick
authors.forename: Paula E
authors.initials: PE
authors.lastname: Schauwecker
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
authors.forename: George M
authors.initials: GM
authors.lastname: Smith
authors.forename: Ron
authors.initials: R
authors.lastname: Mervis
authors.forename: YanFang
authors.initials: Y
authors.lastname: Li
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Barnes
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D002452:Cell Count / Q000379:methods; D004558:Electric Stimulation / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000473:pathology; D066298:In Vitro Techniques; D007395:Interneurons / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D007608:Kainic Acid; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009434:Neural Pathways / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D039943:Neuropilin-2 / Q000172:deficiency* / Q000235:genetics; D018408:Patch-Clamp Techniques / Q000379:methods; D010433:Pentylenetetrazole; D018079:Receptors, GABA / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D016622:Silver Staining / Q000379:methods; D013569:Synapses / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D039943:Neuropilin-2; D018079:Receptors, GABA; C491229:Sema3f protein, mouse; D049452:Green Fluorescent Proteins; D005680:gamma-Aminobutyric Acid; D007608:Kainic Acid; D010433:Pentylenetetrazole