Reduced hippocampal inhibition and enhanced autism-epilepsy comorbidity in mice lacking neuropilin 2.

Autor:	Eisenberg C; Department of Biological Sciences, Rutgers University, Newark, NJ, 07102, USA., Subramanian D; Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA.; Department of Molecular, Cell and Systems Biology, University of California Riverside, Riverside, California, CA, 92521, USA., Afrasiabi M; Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA., Ziobro P; Department of Biological Sciences, Rutgers University, Newark, NJ, 07102, USA.; Department of Psychology, Rutgers University, Newark, NJ, 07102, USA., DeLucia J; Department of Biological Sciences, Rutgers University, Newark, NJ, 07102, USA., Hirschberg PR; Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA., Shiflett MW; Department of Psychology, Rutgers University, Newark, NJ, 07102, USA., Santhakumar V; Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA. vijayas@ucr.edu.; Department of Molecular, Cell and Systems Biology, University of California Riverside, Riverside, California, CA, 92521, USA. vijayas@ucr.edu., Tran TS; Department of Biological Sciences, Rutgers University, Newark, NJ, 07102, USA. tstran@rutgers.edu.
Jazyk:	angličtina
Zdroj:	Translational psychiatry [Transl Psychiatry] 2021 Oct 18; Vol. 11 (1), pp. 537. Date of Electronic Publication: 2021 Oct 18.
DOI:	10.1038/s41398-021-01655-6
Abstrakt:	The neuropilin receptors and their secreted semaphorin ligands play key roles in brain circuit development by regulating numerous crucial neuronal processes, including the maturation of synapses and migration of GABAergic interneurons. Consistent with its developmental roles, the neuropilin 2 (Nrp2) locus contains polymorphisms in patients with autism spectrum disorder (ASD). Nrp2-deficient mice show autism-like behavioral deficits and propensity to develop seizures. In order to determine the pathophysiology in Nrp2 deficiency, we examined the hippocampal numbers of interneuron subtypes and inhibitory regulation of hippocampal CA1 pyramidal neurons in mice lacking one or both copies of Nrp2. Immunostaining for interneuron subtypes revealed that Nrp2 -/- mice have a reduced number of parvalbumin, somatostatin, and neuropeptide Y cells, mainly in CA1. Whole-cell recordings identified reduced firing and hyperpolarized shift in resting membrane potential in CA1 pyramidal neurons from Nrp2 +/- and Nrp2 -/- mice compared to age-matched wild-type controls indicating decrease in intrinsic excitability. Simultaneously, the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) are reduced in Nrp2-deficient mice. A convulsive dose of kainic acid evoked electrographic and behavioral seizures with significantly shorter latency, longer duration, and higher severity in Nrp2 -/- compared to Nrp2 +/+ animals. Finally, Nrp2 +/- and Nrp2 -/- but not Nrp2 +/+ , mice have impaired cognitive flexibility demonstrated by reward-based reversal learning, a task associated with hippocampal circuit function. Together these data demonstrate a broad reduction in interneuron subtypes and compromised inhibition in CA1 of Nrp2 -/- mice, which could contribute to the heightened seizure susceptibility and behavioral deficits consistent with an ASD/epilepsy phenotype. (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)
Databáze:	MEDLINE
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