Two of the most striking features distinguishing human cortical pyramidal neurons (CPNs) from other mammals which are thought to play a role in the emergence of our unique cognitive abilities are: (1) human CPNs receive significantly more excitatory and inhibitory synapses than any other mammalian species including non-human primates and (2) synaptic development is strikingly neotenic in humans, taking years to reach maturation compared to weeks or months in other mammalian species. Our lab identified two human-specific gene duplications called SRGAP2B/C which, by inhibiting all known functions of the ancestral postsynaptic protein SRGAP2A, leads to slower (neotenic) rates of excitatory (E) and inhibitory (I) synaptic maturation and increased E and I synapse number (Charrier et al. Cell 2012; Fossatti et al Neuron 2016). We demonstrated that induction of expression of human-specific genes SRGAP2B/C in mouse CPNs increases specifically the number of cortico-cortical synaptic connections they receive leading to changes in the coding properties of these neurons in vivo as well as improved behavioral performance in a sensory discrimination task (Schmidt et al. Nature 2021). I will also present recent evidence demonstrating the function of human-specific SRGAP2B/C in human neurons as key mediators of synaptic neoteny, using a novel xenotransplantation model, in collaboration with Pierre Vanderhaeghen’s lab (Libé-Philippot et al. Neuron 2024). These results also provide the first evidence that human-specific genes such as SRGAP2B/C are not only relevant to understand human brain evolution but also constitute human-specific disease modifiers.
I will also present new results demonstrating that human-specific SRGAP2B/C genes also act as master regulators of the timing of structural and functional maturation of microglial cells using both humanized mouse models and SRGAP2B/C loss-of-function approaches using human iPSC-derived microglia xenotransplantation in mouse neonatal cortex. Our results demonstrate that SRGAP2B/C-dependent induction of neotenic maturation of microglial cells participates non-cell autonomously to the delayed timing of synaptic maturation in cortical pyramidal neurons. Our results reveal that, during human brain evolution, human-specific genes SRGAP2B/C coordinated the emergence of neotenic features of synaptic development by acting as genetic modifiers in both neurons and microglia.
SPEAKER BIOGRAPHY
Since 2013, Franck Polleux is a Professor of Neuroscience at Columbia University and a Principal Investigator at the Zuckerman Mind Brain Behavior Institute in New York. He obtained his PhD in 1997 at Université Claude Bernard in Lyon France under the supervision of Henry Kennedy and Colette Dehay. He then did his postdoctoral training with Anirvan Ghosh at Johns Hopkins University. From 2002-2010, he started his independent research career at UNC-Chapel Hill, then moved to Scripps Research Institute in La Jolla, CA.
Throughout his scientific career spanning three decades, Dr Polleux has focused on the identification of novel cellular and molecular mechanisms underlying the development and function of synapses, neurons and circuits in the mammalian neocortex. More recently, his lab started studying the genetic basis of human brain evolution by focusing on the role of human-specific gene duplications as genetic modifiers of synaptic connectivity, circuit function and their impact on cognition. His work demonstrates that human-specific genes such as SRGAP2B/C not only represent human-specific modifiers of brain development but also represent unique human-specific disease modifiers in the context of neurodevelopmental disorders such as autism spectrum disorders. In collaboration with the lab of Attila Losonczy, he recently started to study the synaptic and molecular basis of feature selectivity of place cell emergence using mouse CA1 hippocampal pyramidal neurons as a model.
For his numerous scientific contributions, he was awarded several prestigious awards such as the Albert L. Lehninger Research Prize for postdoctoral research, the 2005 NARSAD Young Investigator Award, the 2015 Foundation Roger De Spoelberch Prize, a 2021 Nomis Foundation Award and the 2021 R35 Research Program Award, a career award from the NIH-National Institute of Neurological Disorders and Stroke (NINDS).
