Decreased number of interneurons and increased seizures in neuropilin 2 deficient mice: Implications for autism and epilepsy
Version of Record online: 24 JUL 2008
Wiley Periodicals, Inc. © 2009 International League Against Epilepsy
Volume 50, Issue 4, pages 629–645, April 2009
How to Cite
Gant, J. C., Thibault, O., Blalock, E. M., Yang, J., Bachstetter, A., Kotick, J., Schauwecker, P. E., Hauser, K. F., Smith, G. M., Mervis, R., Li, Y. and Barnes, G. N. (2009), Decreased number of interneurons and increased seizures in neuropilin 2 deficient mice: Implications for autism and epilepsy. Epilepsia, 50: 629–645. doi: 10.1111/j.1528-1167.2008.01725.x
- Issue online: 3 APR 2009
- Version of Record online: 24 JUL 2008
- Accepted May 26, 2008; Early View publication July 24, 2008.
Purpose: 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.
Discussion: 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.