Atypical sensory perception is highly prevalent in individuals with autism spectrum disorder (ASD). Sensory issues can involve hyper- or hypo-reactivity to sensory stimuli, occur across sensory modalities, and are included as a core diagnostic feature for ASD.

A key brain circuit involved in sensory processing is the thalamocortical circuit, which relays sensory information from the thalamus to the cortex. Brain imaging studies have observed altered functional thalamocortical connectivity in autistic individuals, which may contribute to atypical sensory perception. The molecular and cellular mechanisms underlying thalamocortical dysconnectivity in ASD are not understood. In this project, Joris de Wit and colleagues plan to determine the impact of ASD risk genes on the development of a specific thalamocortical circuit.

Neural circuits are composed of different types of neurons connected by synapses. To determine which neuron types and synapses in the thalamocortical circuit are most vulnerable in ASD, de Wit and his team applied their expertise in high-end molecular biology approaches and synapse biology to analyze excitatory postsynaptic protein composition in two main populations of cortical layer 5 (L5) pyramidal neurons in mice: intratelencephalic (IT) and pyramidal tract (PT) neurons. This approach revealed a striking enrichment of proteins encoded by ASD risk genes in IT, but not in PT L5 neurons. IT and PT L5 neurons differ markedly in their thalamic input: IT L5 neurons receive input from the posteromedial thalamic nucleus (POm), a higher-order nucleus thought to integrate sensory, motor and associative information. PT L5 neurons on the other hand receive no or very little POm input. Taken together, these preliminary results¹ suggest that IT L5 neurons and their excitatory input from the POm are vulnerable in ASD. However, whether and how the identified ASD risk genes play a role in correct structural and functional connectivity of this thalamocortical circuit is unknown.

Here, de Wit and colleagues plan to use reconstitution of a split fluorescent reporter across the synaptic cleft² to analyze the impact of ASD risk gene loss-of-function on the formation of specific synaptic contacts between POm and IT L5 neurons in mice. Using optogenetic stimulation and whole-cell recordings, they then aim to assess the effect of loss of ASD risk genes on functional connectivity between POm and IT L5 neurons. How the identified ASD risk genes affect sensory behavior in mouse models is largely unknown. The experiments the team will perform are expected to provide first insight into how these ASD risk genes affect specific thalamocortical connectivity important for sensory perception.

With this work, de Wit’s team expect to determine how ASD risk genes—many of which have synaptic functions—affect connectivity between the higher-order thalamus and IT L5 neurons. Such insights are currently lacking in the ASD field and may eventually provide more focused directions for therapy.

1. Marcasa G. et al. bioRxiv (2024) Preprint
2. Choi J.H. et al. Science 360, 430–435 (2018) PubMed