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Crucial Gene Connects Autism and Epilepsy Through Brain Development


The study supports the idea that alterations in interneuron development may be a key mechanism for the comorbidity between ASD and epilepsy. The results show that failure of Nrp2 development and regulation in interneurons impairs the normal functioning of the hippocampal circuit, leading to ASD-like behaviors and increasing the likelihood of seizures.


Autism Spectrum Disorder (ASD) and epilepsy are conditions that are often seen together, or comorbid, and are thought to share some similar biological mechanisms.


These conditions involve abnormalities in the development and function of a specific type of nerve cell called interneurons, which are responsible for regulating the activity of other nerve cells in the brain.


These abnormalities are called “interneuronopathies” and are strongly associated with both ASD and epilepsy. The presence of seizures and behavioral difficulties in several subtypes of ASD can be explained by changes in the functioning of these neurons, especially inhibitory neurons, which help control the excitability of nerve cells in the brain.

The main type of interneuron involved in this process is GABAergic, which plays a crucial role in the organization and function of a region of the brain called the hippocampus, which is often linked to both ASD and epilepsy.


When interneuron circuits fail to form in the brain, this can impair hippocampal function, leading to an increased risk of seizures and the emergence of behavioral deficits typical of ASD.


In this study, researchers from the University of California Riverside, USA, investigated how failure to develop a receptor, called Neuropilin-2 (Nrp2), on developing interneurons affects hippocampal circuit function and may predispose to seizures and typical ASD behaviors.


Nrp2 is a protein that, during brain development, helps neurons move to the correct regions and connect properly. Specifically, Nrp2 regulates the migration of interneurons, which are cells that help balance excitation and inhibition within the brain.

During embryonic development, the expression of the Nrp2 gene in interneuron precursor cells is controlled by a transcription factor called Nkx2.1, and this regulation allows interneurons to migrate correctly to regions such as the hippocampus and cortex, where they play a key role in modulating neural activity.


When Nrp2 does not function properly, as shown in previous studies, there is a loss of interneurons in the hippocampus, which can result in behavioral deficits typical of ASD and increased susceptibility to seizures.


However, it was not known whether failure of Nrp2 in specific interneurons during their migration to the hippocampus and cortex could result in an ASD-like picture and increased risk of seizures.


To investigate this, the researchers created an experimental mouse model in which Nrp2 was specifically deleted in interneuron precursors derived from the medial ganglionic eminence (MGE), an area of ​​the brain responsible for the formation of certain types of interneurons.


To do this, they used a technique called "Cre-Lox", which allows specific genes to be removed at specific times and locations during development. In the case of this study, the removal of Nrp2 was induced in pregnant mice (pregnant females) by administering a compound called tamoxifen, which activates an enzyme called Cre recombinase.


This enzyme acts by removing Nrp2 only in interneuron precursors during the critical period of migration to the hippocampus, with the aim of minimizing effects on other phases of neural development.


Mice lacking Nrp2 (iCKO) in their interneurons were analyzed for the function of an area of ​​the hippocampus called CA1, to see if the absence of Nrp2 would cause changes in behavior and electrical activity in the brain, leading to a higher risk of seizures.

Fluorescent immunostaining of brain sections from controls D, E and mice lacking Nrp2 (iCKO) F, G, respectively, with anti-PV (marker for interneurons, red) and DAPI (marker for all cell types, blue). E, G) High-magnification images of green boxes in D and F, respectively. H) Quantification of the mean total number of PV+ cells in the hippocampus. I) Quantification of the mean number of PV+ cells per hippocampal region.


The results showed that the lack of Nrp2 in interneurons significantly impaired the migration and number of neurons expressing proteins important for interneuron function, such as parvalbumin, neuropeptide Y, and somatostatin.


As a result, electrical activity in the hippocampus was altered, with a reduction in inhibitory synaptic currents and an increase in excitatory currents, which unbalanced the relationship between excitation and inhibition, a condition known to facilitate the development of seizures.

Representative traces showing spontaneous excitatory postsynaptic currents (sEPSCs) in control and iCKO mice. Note that events are more frequent in iCKO mice.


Although the properties of CA1 pyramidal nerve cells were unchanged in some respects, mice with the Nrp2 deletion showed an increased susceptibility to chemically induced seizures.


In addition, these mice showed significant behavioral deficits, especially in tasks related to social interaction and learning, both behaviors frequently altered in individuals with ASD.

These results show that failure to develop and regulate Nrp2 in interneurons impairs normal hippocampal circuitry, leading to ASD-like behaviors and increasing the likelihood of seizures.


The study supports the idea that alterations in interneuron development may be a key mechanism for the comorbidity between ASD and epilepsy.


In other words, deficiencies in the formation and function of these neurons may be responsible for both the behavioral deficits and the increased propensity for seizures observed in individuals with these conditions.



READ MORE:


Dysregulation of neuropilin-2 expression in inhibitory neurons impairs hippocampal circuit development and enhances risk for autism-related behaviors and seizures

Subramanian D, Eisenberg C, Huang A. et al.  

Mol Psychiatry (2024). 


Abstract:


Dysregulation of development, migration, and function of interneurons, collectively termed interneuronopathies, have been proposed as a shared mechanism for autism spectrum disorders (ASDs) and childhood epilepsy. Neuropilin-2 (Nrp2), a candidate ASD gene, is a critical regulator of interneuron migration from the median ganglionic eminence (MGE) to the pallium, including the hippocampus. While clinical studies have identified Nrp2 polymorphisms in patients with ASD, whether selective dysregulation of Nrp2-dependent interneuron migration contributes to pathogenesis of ASD and enhances the risk for seizures has not been evaluated. We tested the hypothesis that the lack of Nrp2 in MGE-derived interneuron precursors disrupts the excitation/inhibition balance in hippocampal circuits, thus predisposing the network to seizures and behavioral patterns associated with ASD. Embryonic deletion of Nrp2 during the developmental period for migration of MGE derived interneuron precursors (iCKO) significantly reduced parvalbumin, neuropeptide Y, and somatostatin positive neurons in the hippocampal CA1. Consequently, when compared to controls, the frequency of inhibitory synaptic currents in CA1 pyramidal cells was reduced while frequency of excitatory synaptic currents was increased in iCKO mice. Although passive and active membrane properties of CA1 pyramidal cells were unchanged, iCKO mice showed enhanced susceptibility to chemically evoked seizures. Moreover, iCKO mice exhibited selective behavioral deficits in both preference for social novelty and goal-directed learning, which are consistent with ASD-like phenotype. Together, our findings show that disruption of developmental Nrp2 regulation of interneuron circuit establishment, produces ASD-like behaviors and enhanced risk for epilepsy. These results support the developmental interneuronopathy hypothesis of ASD epilepsy comorbidity.

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