A human-specific modifier of cortical connectivity and circuit function

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Schmidt ERE et al. Nature. 2021 November

Back in the early 1970s, it was hypothesized that human-specific cognitive abilities could be affected by changes in gene expression levels over the course of brain development and maturation.^1,2 It was only in recent years, though, that scientists demonstrated that duplications of human-specific genes are indeed associated with human brain development.^3,4 One of such genes is Slit-Robo GTPase activating protein 2A (SRGAP2A), whose ancestral copy – also present in rodents and primates – duplicated only in the human lineage to form two truncated paralogs: SRGAP2B and SRGAP2C.⁵

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Interestingly, while SRGAP2A is involved in maturation of both excitatory and inhibitory synapses received by cortical pyramidal neurons (PNs), SRGAP2B and SRGAP2C inhibit these functions. More specifically, SRGAP2C binds to SRGAP2A and targets this heterodimer to the proteasome degradation pathway, thereby effectively reducing SRGAP2A protein levels in dendrites of cortical PNs. This ultimately leads to increased synaptic density and protracted synapse maturation throughout adulthood, thus favoring human brain development.⁵

Mice lack SRGAP2C and, as such, they represent valuable models to study how the expression of this gene can modify cortical circuit connectivity and function and behavioral performance. In their paper, freshly published in Nature, Schmidt and colleagues use conditional Knockin mice to specifically express human SRGAP2C in all cortical PNs to unveil the role of this gene’s emergence in human brain development. Computational modelling revealed that conditional SRGAP2C-expressing mice display an altered cortical circuit connectivity due to an increased number of local and long-range cortical inputs received by layer 2/3 PNs. Moreover, they possess an enhanced ability to discriminate two textures using their whiskers (i.e., a cortex-dependent sensory-discrimination task) compared to wild-type mice. Taken all together, these findings suggest that the advent of SRGAP2C has contributed to the evolutionary emergence of specific structural and functional traits of the human cortex.⁶

Of note, the genetically engineered mice used in this study were generated by genOway, designer and provider of multiple preclinical models in several research areas, including immuno-oncology, metabolism, cardiovascular diseases, and neuroscience.

References:

1. 1. Liu, X. et al. Extension of cortical synaptic development distinguishes humans from chimpanzees and macaques. Genome Res. 22, 611–622 (2012).
2. King, M.-C. & Wilson, A. C. Evolution at Two Levels in Humans and Chimpanzees: Their macromolecules are so alike that regulatory mutations may account for their biological differences. Science 188, 107–116 (1975).
3. Sudmant, P. H. et al. Diversity of Human Copy Number Variation and Multicopy Genes. Science 330, 641–646 (2010).
4. Fortna, A. et al. Lineage-Specific Gene Duplication and Loss in Human and Great Ape Evolution. PLoS Biol 2, e207 (2004).
5. Schmidt, E. R. E., Kupferman, J. V., Stackmann, M. & Polleux, F. The human-specific paralogs SRGAP2B and SRGAP2C differentially modulate SRGAP2A-dependent synaptic development. Sci Rep 9, 18692 (2019).
6. Schmidt, E. R. E. et al. A human-specific modifier of cortical connectivity and circuit function. Nature 599, 640–644 (2021).