Humanization of SRGAP2C expression increases cortico-cortical connectivity and reliability of sensory-evoked responses in the mouse brain

The remarkable cognitive abilities characterizing humans has been linked to unique patterns of connectivity characterizing the neocortex. Comparative studies have shown that human cortical pyramidal neurons (PN) receive a significant increase of synaptic inputs when compared to other mammals, including non-human primates and rodents, but how this may relate to changes in cortical connectivity and function remains largely unknown. We previously identified a human-specific gene duplication (HSGD), that, when induced in mouse cortical PNs drives human-specific features of synaptic development, including a correlated increase in excitatory (E) and inhibitory (I) synapse density. However, the origin and nature of this increased connectivity and its impact on cortical circuit function was unknown. Here, using a combination of transgenic approaches and quantitative monosynaptic tracing, we demonstrate that humanization of expression in the mouse cortex leads to a specific increase in local and long-range cortico-cortical inputs received by layer 2/3 cortical PNs. Moreover, using 2-photon imaging in the barrel cortex of awake mice, we show that humanization of SRGAP2C expression increases the reliability and selectivity of sensory-evoked responses in layer 2/3 PNs. Our results suggest that the emergence of during human evolution led to increased local and long-range cortico-cortical connectivity and improved reliability of sensory-evoked cortical coding.