The search for therapies for autism spectrum disorder (ASD) might benefit from discovering reliable endophenotypes in animal models, especially if these could be adapted to in vitro assays and validated in behaving animals. Despite disagreement concerning how best to measure or interpret it, there is broad agreement that altered brain activity in ASD reflects changes in the balance between excitation and inhibition (E/I) in brain circuits. A major impediment to understanding E/I balance and other changes in neuronal activity within brain circuits of individuals with ASD and genetically modified mouse models of ASD is that it is difficult to separate the primary effects of the condition from subsequent compensatory changes acting on those same circuits. This is exacerbated by the fact that compensation may evolve over development and have different effects in different brain regions.
Sacha Nelson’s lab has recently developed a slice culture platform for monitoring network activity via calcium imaging. Using this platform, they are investigating how reduced activity shifts E/I balance and leads to epileptiform activity. They have identified multiple forms of homeostatic plasticity that contribute and discovered a family of transcription factors that normally prevent this excessive homeostatic response. An important outcome of this work is that they have developed quantitative, reproducible measures that reliably capture changes in network activity and that correlate with biophysical measures of E/I balance.
Nelson and his team now propose to use this same approach to test E/I balance and its modification by homeostatic plasticity in four established ASD mouse models (16p11.2 deletion, Cntnap2-/-, Syngap1+/- and Grin2b+/- mice). They plan to compare two different regions (sensory cortex and hippocampus) at several stages of circuit maturation using measures of neuronal synchrony and response stereotypy that they have developed. They will then validate the in vivo relevance of these observations by using telemetry to monitor network activity and seizures in awake behaving animals.
Together, these pilot experiments will establish whether and which features of in vitro activity are likely to have the greatest validity for use in subsequent screening platforms. Findings from these studies will also provide pathophysiological insight into the interplay between ASD circuit disruptions, regional circuit differences and developmental compensation mechanisms.
