Abstract
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.
Highlights
Epilepsy and autism spectrum disorders (ASD) exhibit a remarkable degree of comorbidity, suggesting shared pathological mechanisms [1, 2]
Deletion of the neuropilin 2 (Nrp2) ligand, semaphorin 3 F (Sema3F), in GABAergic neurons resulted in increased seizure susceptibility [24] and development of autism-like behaviors [25], suggesting that mice with deficient Nrp2 signaling could serve as a model to assess inhibitory circuit dysregulation associated with the propensity for autism/seizure phenotypes
Synaptic Inhibition is reduced in mice lacking Nrp2 In light of the marked decrease in all three interneuronal classes in hippocampal CA1 of Nrp2−/− mice, we examined whether the deletion of Nrp2 alters synaptic inhibitory inputs to CA1 pyramidal cells (Fig. 4A–D)
Summary
Epilepsy and autism spectrum disorders (ASD) exhibit a remarkable degree of comorbidity, suggesting shared pathological mechanisms [1, 2]. The link between the factors regulating the formation of GABAergic circuits during development, their impact on cellular and synaptic inhibition, and the risk for developing seizures and autism-like behavioral traits remain to be established. Mice with Nrp deletion (Nrp2−/−) were reported to have reduced GABAergic neurons in hippocampal subfields [19] and were found to be impaired in social object recognition and social novelty preference [20] consistent with a potential link between the reduction in interneurons and ASD-like phenotype. Deletion of the Nrp ligand, semaphorin 3 F (Sema3F), in GABAergic neurons resulted in increased seizure susceptibility [24] and development of autism-like behaviors [25], suggesting that mice with deficient Nrp signaling could serve as a model to assess inhibitory circuit dysregulation associated with the propensity for autism/seizure phenotypes
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