Although the clinical manifestations of autism spectrum disorders are highly variable and their underlying causes are still largely unknown, accumulating evidence implicates variations in genes encoding synaptic proteins, which function at the connections between brain cells. Altered synaptic proteins can lead to faulty wiring in the developing brain.
Of particular interest are connections between the prefrontal cortex (PFC) and striatum, but little is known about the normal development of these circuits. People harboring the 16q21 microdeletion, in which a single gene (CDH8, which encodes cadherin 8) is deleted, have autism and learning disabilities.
Deanna Benson, George Huntley and their colleagues at the Icahn School of Medicine at Mount Sinai in New York investigated the role of CDH8 in the development of PFC-striatal circuitry and how the loss of CDH8 may contribute to cortical circuit disruptions associated with autism. The investigators used high-resolution in situ hybridization and anatomical tracers to show that CDH8 is expressed within projection neurons in cortical layer 5 and in the target neurons of the dorsal striatum as connections between these two areas are forming.
They also found that CDH8 is concentrated at synapses in vivo and that lowering the expression of CDH8 in cultured neurons produces abnormal connections. These findings support the idea that CDH8-mediated adhesion contributes to the assembly of normal cortico-striatal circuits.
To test this idea further, Benson and Huntley generated a mouse line in which they aim to selectively eliminate CDH8 from particular neuronal populations. This allows them to assess CDH8’s impact on cortico-striatal connections in vivo and on the development of autism-related behaviors.
