Despite recent progress, the development of tailored therapies for autism spectrum disorder (ASD) requires identifying the causal links between genetic, cellular and neural circuit defects that lead to behavioral and cognitive symptoms. One attractive hypothesis central to this proposal is that a disruption in the human-specific extended timing (neoteny) of synaptic development in cortical circuits could be a key mechanism underlying some forms of ASD. Pierre Vanderhaeghen, Vincent Bonin and Franck Polleux will test this hypothesis by focusing on SYNGAP1 haploinsufficiency, a major genetic cause of ASD.

Human cortical neurons display strikingly prolonged synaptic development compared with those of other mammals. By prolonging the refinement of cortical circuits, human synaptic neoteny could contribute to advanced cognitive and social functions. Conversely, accelerated synapse development and postnatal brain overgrowth have been observed in some cases of ASD suggesting that accelerated synaptogenesis could contribute to ASD pathogenesis, but this has remained speculative.

Vanderhaeghen, Bonin and Polleux recently developed models of xenotransplantation of human cortical pyramidal neurons (CPNs) in the mouse cortex, in which the human CPNs develop morphological, physiological and functional properties over a significantly extended timing, therefore retaining juvenile, neotenic properties in vivo. Using this unique model, they found that human CPNs haploinsufficient for SYNGAP1 display accelerated synaptic development and premature acquisition of visual responses compared to control human CPNs, consistent with a disruption of their neotenic development. Moreover, they found that the human-specific genes SRGAP2B/C promote human synaptic neoteny by regulating the synaptic levels of SYNGAP1, and therefore act as human-specific modifiers of the phenotypic expression of SYNGAP1 haploinsufficiency.

Here, Vanderhaeghen, Bonin and Polleux propose to use a unique combination of human-to-mouse cortical xenotransplantation and transgenic mouse models displaying humanized expression of SRGAP2C, to test the hypothesis that accelerated synaptic developmental timing in SYNGAP1 haploinsufficiency alters the temporal patterning of development and plasticity of cortical circuits and behavioural maturation, and that this is modified by the human-specific genes SRGAP2B/C. Specifically, using their recently established xenotransplantation model, they will examine the effects of SYNGAP1 haploinsufficiency on early sensory function and plasticity of human CPNs xenotransplanted into the mouse cortex, and how these are modulated by SRGAP2 genes. In parallel, they will combine mouse genetic models of SYNGAP1 haploinsufficiency together with humanized SRGAP2C expression that we generated, to determine the impact of SYNGAP1 haploinsufficiency and SRGAP2C-induced neoteny on the early development of cortical circuits and behavioral maturation.

This project will reveal how human-specific features of synaptogenesis impact the early functional development and plasticity of cortical circuits and behavioral maturation in SYNGAP1 haploinsufficiency. It will provide novel insights on features of ASD phenotypic expression at the circuit level, could lead to novel therapeutic avenues and help determine when they might be most effective, and lay the foundation for more studies linking human brain neoteny with other forms of ASD.