In addition to social challenges and communication difficulties, a commonly associated feature of autism spectrum disorder (ASD) is alterations in sensory function, including changes in touch, vision and auditory functions. These sensory changes might contribute to ASD core symptoms and/or interfere with overall quality of life.

Mutations or deletions in human MEF2C produce a syndromic form of ASD. Christopher Cowan’s lab at Medical University of South Carolina (MUSC) generated a new mouse model of MEF2C haploinsufficiency syndrome (MCHS), which displays deficits in social behavior and ultrasonic vocalizations, as well as increased repetitive behavior, hyperactivity and other phenotypes reminiscent of symptoms observed in MCHS individuals¹.

The MCHS mice also show changes in sensory cortex excitatory neuron gene expression and synaptic transmission. However, in addition to being expressed in neurons, MEF2C is also detected in macrophages and microglia—a critical population of macrophage-like immune cells in the brain that are important for typical neural circuit development. Cowan’s group observed a significant increase in the microglial activation marker, Iba1, in MCHS mice as well as dysregulation of numerous microglia-associated genes. Furthermore, conditional, early-postnatal deletion of one copy of Mef2c in microglia and macrophage populations produces mice with social behavior deficits and repetitive behaviors¹, suggesting a key role for MEF2C in neural immune cells during development. In the visual system, proper microglial activity is required for the development and refinement of the retinogeniculate circuit and the maintenance of photoreceptor cells. Similarly, macrophages in the cochlea and peripheral auditory nerve are critical for the development and refinement of neural circuits and hearing. In collaboration with Hainan Lang’s lab at MUSC, they found that MEF2C is expressed in cochlear macrophages. They also detected deficits in auditory nerve function in MCHS mice.

In the current project, Cowan, Hainan Lang and Bärbel Rohrer plan to extend these initial findings and further examine the role of MEF2C-related neuroimmune dysfunction in sensory system development and function. Specifically, they aim to explore the impact of MEF2C hypofunction on the development and function of auditory and visual systems. They also plan to determine whether suppression of microglial/macrophage hyperactivation in MCHS mice rescues behavioral phenotypes and sensory system dysfunction.

Findings from these studies are expected to lead to a greater understanding of the links between neuroimmune dysfunction and behavioral, sensory and synaptic deficits in syndromic autism. They could also provide evidence for a candidate neuroimmune-based treatment strategy for MCHS.

1. Harrington A.J. et al. Biol. Psychiatry 88, 488-499 (2020) PubMed