Summary: New research indicates that a shared developmental defect in the formation of inhibitory neural circuits may help explain why autism spectrum disorder (ASD) and epilepsy frequently occur together.
Source: UCR
Epilepsy and autism spectrum disorders (ASD) often co-occur, suggesting overlapping biological causes. Key questions remain: does ASD increase the risk of epilepsy, or do early-life alterations in brain circuitry that cause seizures also promote autistic traits?
Researchers led by Viji Santhakumar, an associate professor in the Department of Molecular, Cell and Systems Biology at the University of California, Riverside, together with Tracy Tran at Rutgers University, investigated these questions in a study published in the journal Translational Psychiatry.
The team tested the hypothesis that abnormalities in inhibitory neurons—cells that suppress and shape neural activity—during brain development could produce circuits that predispose an individual to both ASD and epilepsy. Unlike excitatory neurons that propagate activity forward, inhibitory interneurons act as brakes that sculpt the timing and synchronization of downstream neurons, helping maintain balanced network activity across brain regions such as the hippocampus.
To explore this idea, the researchers created mice with a global mutation that disrupts the normal migration and placement of inhibitory neurons in the developing brain. These mutant mice exhibited a clear reduction in inhibitory signaling within the hippocampus, a brain region essential for memory and cognition. Behaviorally, the mice displayed traits consistent with autism-like phenotypes and showed increased vulnerability to seizures.
Santhakumar and colleagues report fewer inhibitory interneurons in affected circuits, pointing to a developmental failure to establish appropriate inhibitory connectivity. “There may be a developmental abnormality in establishing inhibitory neuron circuits,” Santhakumar said. “If we can identify the molecular pathways responsible, early interventions might preserve inhibitory circuitry and reduce the combined risk of autism and epilepsy.”
The findings support the idea that a common defect in circuit formation—specifically reduced inhibitory neuron number and function in the hippocampus—can underlie both ASD-like behaviors and increased seizure susceptibility. These results motivate additional studies that restrict genetic mutations to particular cell types and developmental windows to clarify whether disrupted neuron migration or later failures in maintaining circuit connections are most critical in producing autism-epilepsy comorbidity.
Funding for the project included a grant from the New Jersey Governor’s Council for Medical Research and Treatment of Autism. The study’s lead authorship is shared by Deepak Subramanian, an assistant project scientist at UC Riverside, and Viji Santhakumar.
The research article is titled, “Reduced hippocampal inhibition and enhanced autism-epilepsy comorbidity in mice lacking neuropilin 2.” Coauthors include Tracy Tran and Deepak Subramanian, followed by Carol Eisenberg, Patryk Ziobro, Jack DeLucia, Michael W. Shiflett (Rutgers University), and Milad Afrasiabi and Pamela R. Hirschberg (Rutgers New Jersey Medical School). Subramanian, Eisenberg, and Afrasiabi contributed equally to the work.
About this epilepsy and autism research news
Author: Iqbal Pittalwala
Source: UCR
Contact: Iqbal Pittalwala – UCR
Image: The image is in the public domain
Original Research: Open access. “Reduced hippocampal inhibition and enhanced autism-epilepsy comorbidity in mice lacking neuropilin 2” by Viji Santhakumar et al., Translational Psychiatry
Abstract
Reduced hippocampal inhibition and enhanced autism-epilepsy comorbidity in mice lacking neuropilin 2
Neuropilin receptors and their semaphorin ligands are critical regulators of brain circuit development, guiding processes such as synapse maturation and the migration of GABAergic interneurons. Variations at the neuropilin 2 (Nrp2) gene locus have been reported in patients with autism spectrum disorder, consistent with a developmental role for this pathway.
Mice lacking Nrp2 show autism-like behavioral deficits and an increased tendency to develop seizures. To investigate the underlying pathophysiology, the study examined interneuron populations in the hippocampus and assessed inhibitory control over CA1 pyramidal neurons in animals missing one or both copies of Nrp2.
Immunostaining revealed that Nrp2−/− mice have reduced numbers of parvalbumin-, somatostatin-, and neuropeptide Y–expressing interneurons, particularly within the CA1 region. Whole-cell electrophysiological recordings showed decreased firing rates and a hyperpolarized shift in the resting membrane potential of CA1 pyramidal neurons in both Nrp2+/− and Nrp2−/− mice compared with wild-type controls, indicating lowered intrinsic excitability. Concurrently, the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) were reduced in mice deficient for Nrp2.
When challenged with a convulsive dose of kainic acid, Nrp2−/− mice exhibited seizures with significantly shorter latency, longer duration, and greater severity than wild-type animals. Moreover, both Nrp2+/− and Nrp2−/− mice—but not Nrp2+/+ controls—showed impaired cognitive flexibility on a reward-based reversal learning task, a deficit linked to hippocampal circuit dysfunction.
Collectively, these data indicate a widespread reduction in multiple interneuron subtypes and weakened inhibition in hippocampal CA1 of Nrp2−/− mice. Such circuit-level deficits may underlie the combined phenotype of heightened seizure susceptibility and behavioral features resembling ASD, highlighting a potential shared developmental mechanism for autism-epilepsy comorbidity.