Autism spectrum disorder (ASD) affects one in 59 children in the United States. In addition to social challenges and repetitive behaviors, children and adults with ASD display a diverse set of motor impairments. Remarkably, half of children with ASD show a concurrent occurrence of hypotonia¹. Affected infants, often referred to as “floppy babies,” have lower muscle strength and may appear “hyperactive” because of the inability to control posture.

Hypotonia in early ages is believed to contribute to the development of many ASD-associated features, including poor motor skills, difficult speech production and social challenges. However, mechanisms of ASD-associated hypotonia are not well understood. Considering that muscle tone is critically controlled by the neuromuscular junction (NMJ), a synapse between motoneurons and muscles, Lin Mei and his colleagues posit that NMJ changes may serve as a pathological mechanism of ASD-associated hypotonia.

In preliminary studies, Mei’s team found that NMJs were fragmented, poorly innervated and that neuromuscular transmission was compromised in Cul3 mutant mice, a mouse model of autism. Such findings reveal a novel mechanism for ASD-associated hypotonia and identify the NMJ as a target for ASD risk genes.

To further test this hypothesis, Mei and his collaborators plan to: (1) determine the time courses of muscle weakness, NMJ decline and agrin signaling reduction in Cul3 mutant mice, (2) investigate whether restoring agrin signaling diminishes NMJ deficits in Cul3 mutant mice and (3) determine whether restoring Cul3 in muscles mitigates muscle weakness and motor and social deficits.

By investigating how Cul3 mutation causes muscle weakness, this project is expected to provide insight into pathological mechanisms of hypotonia, a feature often observed in children with ASD. The results will not only identify the NMJ as a cellular target but also reveal an unexpected molecular mechanism — agrin signaling impairment for hypotonia, motor and/or social challenges. Such results may provide new leads for the development of diagnostic markers and therapeutic interventions for ASD-associated muscle weakness.