A recent study sheds light on how the gene neuropilin2 influences the behavioral changes linked to autism spectrum disorder and epilepsy.
The gene neuropilin2 produces a receptor that is essential for cell interactions in the brain and is crucial for the formation of neural pathways. This gene regulates both the movement of inhibitory neurons and the establishment and upkeep of synapses in excitatory neurons, both of which are vital for proper brain function.
Conducted by neuroscientist Viji Santhakumar from the University of California, Riverside, in collaboration with researchers at Rutgers University in Newark, New Jersey, this study provides new insights into how this gene affects behavioral changes associated with autism spectrum disorder and epilepsy. The findings, published in Nature Molecular Psychiatry, could pave the way for future treatments that address some of the more challenging symptoms of these often co-occurring conditions.
While earlier studies have connected mutations in neuropilin2 to neurological disorders such as autism and epilepsy, the underlying mechanisms had remained largely unexplored. In this study, Santhakumar and her team developed a specialized mouse model with an “inhibitory neuron selective knockout” to investigate what happens when the neuropilin2 gene is eliminated. They discovered that the lack of neuropilin2 hinders the movement of inhibitory neurons, causing a disruption in the balance of excitatory and inhibitory signals in the brain.
“This disruption results in behaviors similar to those seen in autism and a heightened risk of seizures,” explained Santhakumar, who is also a professor of molecular, cell, and systems biology. “Our findings emphasize how just one gene can affect both excitatory and inhibitory systems in the brain. We demonstrate that interference with the development of inhibitory circuits is enough to trigger behaviors related to autism and the occurrence of epilepsy. By enhancing our understanding of how neuropilin2 operates in brain circuitry formation, we can potentially create more tailored therapies for various aspects of these disorders.”
A distinctive feature of this study is the emphasis on the movement of inhibitory neurons, a process significantly influenced by neuropilin2. By specifically removing neuropilin2 during a critical developmental phase, the researchers observed deficiencies in the inhibitory regulation of the circuit, which resulted in reduced behavioral flexibility, challenges in social interactions, and an increased risk of seizures.
The results indicate that focusing on certain stages of neuronal development could provide new opportunities for therapeutic interventions, possibly preventing the onset of these disorders if identified early.
“By pinpointing the role of inhibitory circuit formation, we might develop treatment strategies that improve outcomes for individuals with autism, particularly those who also experience seizures,” Santhakumar stated.
Santhakumar joined UCR in 2018 from Rutgers University to broaden her research goals, aiming to gain a comprehensive understanding of brain circuit function in health and disease, as well as the biological mechanisms contributing to developmental brain disorders. This collaborative study utilized advanced methodologies for both behavioral and physiological evaluations. The research was supported by funding from the Rutgers Brain Health Institute and the New Jersey Council for Autism Spectrum Disorders.
“This research marks a significant advancement in the comprehension of the genetic and circuit-based foundations of autism and epilepsy,” said Santhakumar. “It is vital to continue examining the intricate mechanisms that regulate circuit development and maintenance, as this insight could eventually lead to new interventions for a variety of developmental disorders, including autism, attention-deficit/hyperactivity disorder, and schizophrenia.”
Santhakumar’s co-authors on the study include Deepak Subramanian, Andrew Huang, and Samiksha Komatireddy from UCR; as well as Carol Eisenberg, Jiyeon Baek, Haniya Naveed, Michael W. Shiflett, and Tracy S. Tran from Rutgers University. Both Subramanian and Eisenberg contributed equally to the research.
The title of the paper is “Dysregulation of neuropilin-2 expression in inhibitory neurons impairs hippocampal circuit development and enhances risk for autism-related behaviors and seizures.”
