GENE X ENVIRONMENT INTERACTION IN A NEURONAL MODEL OF SHANK3-RELATED AUTISM SPECTRUM DISORDER

Non-syndromic Autism Spectrum Disorder (ASD) is caused by a complex interaction between genetic predisposition and environmental influences during early development. Among high-confidence ASD gene, Shank3 plays a key role in organizing excitatory synapses and regulating neuronal circuit assembly. As SHANK3 deficiency determines a mild phenotype in neuronal models, environmental factors are suspected to contribute to the development of clinically manifest ASD in humans carrying Shank3 mutations. In this regard, early-life stress is increasingly associated with the development of psychiatric disorders later in life.
To investigate the interaction between Shank3 haploinsufficiency and stress, primary neuronal cultures derived from wild-type and Shank3 mutant mice were exposed to corticosterone for 72 h, which activates a glucocorticoid receptor response affecting neuronal maturation in vitro. Neuronal and synaptic excitability were assessed at the end of corticosterone treatment using whole-cell patch-clamp electrophysiology and MEA recordings at DIV 17 and 21.
Corticosterone induced marked alterations of neuronal activity at multiple scales. At single-neuron level, patch-clamp recordings showed alterations in intrinsic excitability and synaptic transmission, including reduced spiking activity and excitatory synaptic transmission. MEA recordings revealed a suppression of global network activity, consisting of decreased firing rates, reduced burst frequency, and impaired synchronization across the neuronal network. These findings indicate that pharmacological activation of a stress response weakens both single neuron and network excitability in neuronal cultures, suggesting that, in humans, genetic risk factors such as a Shank3 mutations may act in concert with early-life stressful stimuli to drive neurodevelopmental delay, a typical neurological feature of ASD.