Altered dopamine neurotransmission and repetitive behaviours in Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a heritable neuropsychiatric disorder characterized by core behavioral symptoms.

Repetitive behaviors are clinically relevant but less studied; thus, there is a critical need for innovative mechanistic studies and the identification of disease-modifying strategies.Animal models of syndromic monogenic ASD, such as the Fragile X syndrome (FXS) and the eIF4E mice developed by us, have demonstrated that altered protein synthesis is one of the underlying molecular causes of syndromic ASD.

Clinical studies showed that repetitive behaviors in ASD are associated with a defective striatum.

Since dopamine (DA) regulates striatal synaptic plasticity and behaviors, the central hypothesis of this research grant is that aberrant DA neurotransmission impairs striatal functions and results in repetitive and perseverative behaviors.The eIF4E mouse model will be employed to investigate impaired DA neurotransmission in acute striatal slice with Fast Scan Cyclic Voltammetry (FSCV), patch-clamp, and optogenetic recordings and biosensors in combination with multiphoton microscopy (AIM1); and in vivo with fiber photometry recordings during ASD-like behaviors (AIM2).

Finally, we will extend our discoveries to the FXS model, the most common monogenic ASD, to determine if DA dysregulations are a common pathogenic mechanism in ASD.Our results will contribute to identifying novel mechanism-based therapeutics and clinical diagnostic markers.