Recent advances in our understanding of autism spectrum disorder (ASD) risk genes have shown that many genes implicated in ASD susceptibility affect early steps in neurodevelopment. However, causally linking such neurodevelopmental disruptions to subsequent alterations in ASD-relevant neural circuits and behavioral outcomes, which is critical for a mechanistic understanding of ASD and the development of effective therapeutic interventions, has proven difficult. This gap between early developmental changes and subsequent emergent circuit and behavioral dysfunction is exemplified by MEF2C, a gene strongly associated with ASD and related neurodevelopmental disorders.

MEF2C encodes a neuronal activity-responsive transcription factor (TF) that serves as a central node in a convergent molecular pathway, frequently dysregulated in ASD, through which neural activity controls synaptic development and function. Heterozygous MEF2C mutations have been linked to idiopathic autism and give rise to MEF2C haploinsufficiency syndrome (MCHS), characterized by various ASD symptoms. However, how MEF2C-associated gene expression and neurodevelopmental disruptions give rise to subsequent ASD-relevant phenotypes remains unclear. While Mef2c dysfunction in both cortical excitatory neurons and parvalbumin (PV)-expressing cortical GABAergic interneurons (INs) underlies a subset of phenotypes in MCHS model models, the precise timing of the initial gene expression changes that occur in heterozygous Mef2c mutant mice, and how these changes affect brain development and behavior, are not known.

Building on the laboratory’s longstanding interest in MEF2C function, as well as evidence implicating both inhibitory and excitatory neuron dysfunction in a range of neuropsychiatric disorders, including ASD, Michael Greenberg and colleagues will seek to investigate the nature and phenotypic consequences of early of MEF2C haploinsufficiency in inhibitory interneurons and excitatory neurons. Tracing of the subsequent circuit, systems-level, and behavioral consequences of Mef2c-sensitive neuron dysfunction will be enabled by the complimentary expertise of the Sandeep Datta lab, leaders in the fields of data-driven behavioral analysis and temporal correlation with neural activity recordings. To this end, the Greenberg lab proposes to 1) characterize the developmental onset of neural gene expression dysregulation in MCHS mice, 2) define the window for Mef2c-sensitive neuron maturation and resulting circuit and behavioral effects, and 3) longitudinally trace the cellular, systems and behavioral consequences of Mef2c-sensitive neuronal dysfunction. These proposed studies will thus causally link MEF2C-dependent disruptions in early neuron development and subsequent ASD-relevant circuit and behavioral dysfunction in MCHS, thereby advancing our understanding of the etiology of a range of syndromic and non-syndromic ASDs and providing new opportunities for the development of therapeutic strategies to alleviate aspects of ASD pathology.