Development, maintenance, and human-specific evolution of cortical circuits

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ABSTRACT Over the past two decades, my laboratory has focused on the identification of novel molecular and cellular mechanisms underlying the development, maintenance (Project 1) and human-specific evolution (Project 2) of cortical circuits. In Project 1, we propose to study the role of novel molecular effectors regulating the function of the two most abundant organelles in neurons: the endoplasmic reticulum and mitochondria. We discovered that these two organelles are morphologically and functionally very different in axons and dendrites. Even more recently, we identified a novel tethering protein Pdzd8 mediating specialized contacts between these two organelles. ER-mitochondria contacts (ERMCs) are emerging as unique biochemical and physiological signaling platforms in most cells and we discovered that in dendrites of pyramidal neurons, ERMCs play critical roles in regulating synaptically-evoked Ca2+ dynamics (Hirabayashi et al., Science 2017). We are now proposing to use an array of new techniques to determine the role of Pdzd8-dependent ER-mitochondria coupling on dendritic integration, synaptic plasticity and their impact on the emergence of feature selectivity in CA1 PNs. Since 2010, we have also initiated a new paradigm to provide insights into one of the most challenging questions in Neuroscience: ‘what makes the human brain unique?’. In particular, our work tackled whether or not the uniqueness of the human cortical circuits has molecular and physiological determinants at the synaptic level. In Project 2, we propose to continue the new paradigm we implemented starting to tackle this question, by studying the role of human-specific gene duplications (HSGDs) as potential genetic modifiers of circuit development and function. The first example of such an HSGD acting as a human-specific modifier of synaptic development and cortical circuit architecture came from our study on SRGAP2A and its human-specific paralog SRGAP2C. Humanization of SRGAP2C expression in mouse cortical pyramidal neurons phenocopies a partial loss of function of SRGAP2A and leads to the emergence of phenotypic traits characterizing human cortical circuits, protracted period of E and I synaptic maturation and increased density of both types of synapses. Our most recent results demonstrate that SRGAP2C increases specifically the formation of cortico-cortical synapses onto layer 2/3 PNs, increased reliability of sensory coding and improved behavioral performance in tasks involving sensory discrimination (Schmidt et al. bioRxiv (2020); Nature in press). We propose to explore other aspects of SRGAP2A functions and how humanization of SRGAP2C modulates them, including their role in microglial cells where both are expressed and in synaptic plasticity within adult cortical circuits. We will also extend this paradigm to other human-specific gene duplications as potential modifiers of cortical circuit development, limiting our scope to 4 other genes expressed in maturing and adult postmitotic neurons in the mouse and human cortex. Our projects will tackle with unprecedented relevance the relationship between genes, circuit architecture, circuit function and behavior in the framework of human cortical circuit evolution.