How Are Epilepsy and Autism Linked?

Summary: A common underlying defect in the formation of neural circuitry may contribute to the development of both autism and epilepsy, researchers report.

Source: UCR

Epilepsy and autism spectrum disorders, or ASD, show a remarkable degree of comorbidity and may share pathological mechanisms. Questions that have bogged down scientists about these disorders include: Does autism lead to an increase in epilepsy? Or does epilepsy alter the brain circuit, which then leads to autism?

Viji Santhakumar, an associate professor in the Department of Molecular, Cell and Systems Biology at the University of California, Riverside, in collaboration with Tracy Tran at Rutgers University have tackled these questions in a paper published in the journal Translational Psychiatry.

“One hypothesis is that during brain development, inhibitory neurons, which regulate brain rhythms, develop in an abnormal manner,” Santhakumar said. “If this is true, then how the brain circuit gets set up is abnormal, which may lead to both autism and epilepsy.”

Santhakumar and her team focused on inhibitory neurons in mice. She explained that unlike excitatory neurons that lead to a forward propagation of information, inhibitory neurons work like a brake by suppressing and sculpting the activity of downstream neurons.

The researchers generated mice with a global mutation in all cells that prevented the inhibitory neurons from migrating to their normal location in mature brain circuits. Not surprisingly, they found a reduction in inhibitory currents in the hippocampus, a region of the brain known for memory function. Notably, the mutant mice showed behavioral traits associated with ASD and were more prone to seizures. 

This shows a brain surrounded by lightening
Notably, the mutant mice showed behavioral traits associated with ASD and were more prone to seizures. Image is in the public domain

“We found fewer inhibitory neurons in the brain circuit,” Santhakumar said. “There may be a developmental abnormality in establishing inhibitory neuron circuits. If we can identify what the molecular pathways are, we may be able to intervene early and make sure the inhibitory circuit is maintained. How the circuit develops may play a key role in the co-occurrence of autism and epilepsy. Understanding these mechanisms may help develop more targeted cures.”

Results of the study suggest that a common underlying defect in circuit formation could contribute to both ASD and epilepsy. The findings of the current study open the doors for future work to test whether mutations, when restricted to specific cell types and developmental periods, can help distinguish between the role of inhibitory neuron migration and maintenance of circuit connections in the development of ASD or epilepsy.     

Santhakumar was supported in this research by a grant from the New Jersey Governor’s Council for Medical Research and Treatment of Autism.

The research paper, on which Deepak Subramanian, an assistant project scientist at UC Riverside, shares lead authorship, is titled, “Reduced hippocampal inhibition and enhanced autism-epilepsy comorbidity in mice lacking neuropilin 2.”

Santhakumar, Tran, and Subramanian were joined in the study by Carol Eisenberg, Patryk Ziobro, Jack DeLucia, and Michael W. Shiflett of Rutgers University; and Milad Afrasiabi and Pamela R. Hirschberg of Rutgers New Jersey Medical School. Subramanian, Eisenberg, and Afrasiabi contributed equally to the study.

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


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

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.

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