In a new paper, out now in Molecular Psychiatry, the Andreae lab, together with the Basson lab in the Centre for Craniofacial and Regenerative Biology, show how excitatory and inhibitory synapse development is disrupted in the prefrontal cortex of mice lacking a copy of the autism-associated gene Chd8 and shed light on the underlying processes involved.
There is strong evidence that loss of one copy of the gene CHD8 is associated with autism spectrum disorder (ASD). CHD8 is a chromatin remodeller which regulates the expression of many genes during brain development. To understand how changes in transcription translate into altered brain circuitry, Ellingford et al. focused on a brain region highly implicated in ASD – the prefrontal cortex – and examined synaptic transmission in this area using a haploinsufficient Chd8 mouse model.
They discovered profound, yet dynamic, alterations to both excitatory and inhibitory synaptic transmission onto deep layer neurons, which were maximal during a specific developmental window. Furthermore, the reduced synaptic excitation:inhibition balance led to a reduction in neuronal output. By selectively deleting a copy of Chd8 in different cell types they were able to tease apart cell-type-specific aspects of the phenotype. In addition, Chd8+/- neurons were unable to adequately retune excitatory synaptic transmission in response to reductions in neural activity, but instead showed inappropriate responses to modulating inhibitory transmission.
The new paper demonstrates that homeostatic responses in ASD-relevant neuronal circuitry are both insufficient and aberrant in the Chd8 model. Ellingford et al. go on to propose that dysregulation of homeostatic plasticity may contribute to the altered excitation:inhibition balance in the prefrontal cortex of Chd8+/- mice. The work highlights the need to track down the origins of synaptic dysfunction - whether it arises as a cell-autonomous consequence of, or network adaptation to, a gene mutation.