A platform to identify circuit defects in autism mouse models

  • Awarded: 2018
  • Award Type: Pilot
  • Award #: 572955

Autism spectrum disorder (ASD) is thought to derive from dysfunction of complex neuronal circuits and has a strong genetic component. There is great interest in understanding the links between autism-related genes and circuit-level dysfunctions. A major obstacle to progress in this area is that the relationship between neural circuits and normal brain function remains largely mysterious. To tackle this difficult problem, Meister and colleagues propose to leverage a part of the central nervous system where the links between genes, proteins, circuits and neural function are particularly well understood: the retina.

The retina rivals all other brain areas in complexity: it contains ~100 different types of neuron and over 30 different microcircuits that use almost every neurotransmitter and modulator known to neuroscience. Therefore, it is expected that any mutation or environmental perturbation that causes defects in neuronal circuits will leave a trace in the functions of the retina. If so, one can use the extensive knowledge of retinal microcircuitry and visual processing to quickly dissect the circuit dysfunction and identify the underlying synaptic and cellular defects.

With this guiding hypothesis, Meister and colleagues will screen multiple ASD mouse models — both genetic and environmentally induced — for abnormal visual processing in the retina. The nature of the defects encountered will suggest hypotheses for the underlying circuit mechanisms that will be tested in detail using pharmacology and histology. The knowledge derived from using the retina as a test bed will stimulate other autism research by offering specific cellular or synaptic hypotheses that can be pursued in other brain areas more likely to be causally involved in ASD. In the long term, one can envision a noninvasive test of retinal function for diagnosis of ASD even in very young subjects not yet able to report on visual perceptions.

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