Impact of Species-Specific Synaptic Maturation Timing on Cortical Circuit and Behavioral Development

PROJECT SUMMARY/ABSTRACT Synaptic development in the human brain is strikingly prolonged. This extended developmental timing has been hypothesized to contribute to the uniqueness of the human brain, explaining some of our extraordinary capacity for complex thinking but also our propensity for neuropsychiatric disease. Until recently though, testing the functional impact of synaptic neoteny was limited, as the molecular mechanisms underlying this phenomenon were largely unknown. A molecular candidate is Slit-Robo Rho-GTPase activating protein 2A (SRGAP2A) that is found in the genome of all mammals and has undergone two large segmental gene duplications that encode SRGAP2B and SRGAP2C in humans only. The ancestral gene, SRGAP2A, encodes a postsynaptic protein that promotes the rate of excitatory and inhibitory synapse maturation, while the human-specific SRGAP2B/C inhibit all known functions of SRGAP2A to significantly extend synaptic maturation in mouse and human cortical pyramidal neurons (CPNs). Disrupted timing of synaptic maturation has been associated with diseases such as intellectual disability (ID), for example, with haploinsufficiency in the Synaptic GTPase Activating Protein 1 (SynGAP1) gene. SynGAP1 encodes for a post-synaptic protein that exerts a function opposite to SRGAP2A by slowing down the pace of synaptic maturation. Recently, our lab demonstrated that SRGAP2A and SynGAP1 cross-inhibit their postsynaptic accumulation and this cross-inhibition sets the tempo of synaptic maturation in human and mouse CPNs, demonstrating the need to study ID mutations in the context of human-specific genetic modifiers. These genetic manipulations in which the timing of excitatory synaptic maturation can be accelerated (SynGAP1+/-), prolonged (SRGAP2+/-), or rescued (SRGAP2+/-; SynGAP1+/-) provide a unique opportunity to test the functional impacts of changing the timing of synaptic maturation on the timing of circuit and behavioral maturation. Aim 1 will utilize CRISPR/Cas9 knock-in approaches and electrophysiology to further characterize the morphological and functional maturation of excitatory and inhibitory synaptic maturation in these mice. Aim 2 will determine how the timing of synaptic maturation impacts cortical circuit maturation by measuring the timing of neuronal activity desynchronization using in vivo two-photon Ca2+ imaging. Finally, Aim 3 will evaluate the effect of synaptic maturation timing on the temporal emergence of adult-like behavioral repertoires using an unbiased approach called Motion Sequencing. The proposed studies will provide critical insights into our understanding of human-specific synaptic neoteny and its consequences on the phenotypic expression of neurodevelopmental disorders uniquely affecting humans.