In vivo calcium dynamics in dendritic spines of Shank3 and Scn2a mutant mouse models of autism
- Awarded: 2019
- Award Type: Pilot
- Award #: 611189
A central feature of autism spectrum disorder (ASD) that has emerged from converging lines of evidence is dendritic spine pathology. Genomic studies have revealed risk genes encoding postsynaptic proteins, postmortem data has shown elevated spine density, and electrophysiological work in rodent models have indicated abnormalities in synaptic transmission. However, so far, most synaptic-level characterizations have come from studies in neuronal cultures and brain slices. As synaptic excitability is affected by background activity, neuromodulation and inhibitory inputs in awake behaving animals, it is difficult to predict how ASD-linked genetic alterations might alter dendritic spine function in vivo.
Alex Kwan’s lab has a long-term goal of delineating cortical circuit dysfunction in ASD. To address the question of how ASD-linked mutations affect dendritic spine function in vivo, Kwan and colleagues will use subcellular-resolution two-photon microscopy to measure calcium transients in dendritic spines in the frontal cortex of awake, head-fixed mice.
These experiments will be performed in two mouse models of ASD: Shank3-InsG3680 and Scn2a+/- mice. The Shank3-InsG3680 mouse carries an ASD-linked mutation and has a companion strain with a schizophrenia-linked mutation, therefore enabling a direct comparison between two related neurodisease models1. The Scn2a+/- mouse recapitulates loss-of-function mutations in SCN2A, which have been strongly associated with ASD2. A recent study reported impaired synaptic plasticity and abnormal neural dynamics in Scn2a+/- mice3, though more experiments are needed to delineate its full impact on cortical function. By testing two genetically distinct models of ASD, Kwan and colleagues will determine if altered spine calcium dynamics is a shared pathophysiological mechanism underlying the disorder.
Results from this work are expected to further our understanding of how calcium signaling may be perturbed in dendritic spines in vivo, providing critical insights into mechanisms underlying dendritic spine pathology in ASD.