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Principal Investigator: FRANCK POLLEUX
Organization: COLUMBIA UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2024
Award: $1,196,738
Funding agency: National Institute of Neurological Disorders and Stroke
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.
Terms: <21+ years old><Adult><Adult Human><Affect><Architecture><Axon><Behavior><Behavioral><Biochemical><Brain><Brain Nervous System><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Code><Coding System><Coupling><Degenerative Neurologic Disorders><Dendrites><Development><Disease><Disorder><Encephalon><Endoplasmic Reticulum><Engineering / Architecture><Ergastoplasm><Evolution><FNBP2><Formin-Binding Protein 2><Gene Duplication><Genes><Genetic><Hortega cell><Human><Intracellular Communication and Signaling><KIAA0456><Laboratories><Maintenance><Mediating><Mice><Mice Mammals><Microglia><Mitochondria><Modern Man><Molecular><Morphology><Murine><Mus><Nature><Nerve Cells><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurodevelopmental Disorder><Neurologic Degenerative Conditions><Neurological Development Disorder><Neurons><Neurosciences><Organelles><Performance><Phenocopy><Phenotype><Physiologic><Physiological><Play><Process><Proteins><Pyramidal neuron><Role><SLIT-ROBO GAP 2><SRGAP2><SRGAP2 gene><SRGAP2A><Science><Sensory><Signal Transduction><Signal Transduction Systems><Signaling><Slit-ROBO RHO GTPase-Activating Protein 2><Synapses><Synaptic><Synaptic plasticity><Techniques><Work><adulthood><biological signal transduction><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><density><developmental><gitter cell><hippocampal pyramidal neuron><improved><insight><loss of function><mesoglia><microglial cell><microgliocyte><mitochondrial><neurodegenerative illness><neurodevelopmental disease><neuronal><novel><paralog><paralogous gene><perivascular glial cell><postmitotic><sensory discrimination><social><social role><synapse><trait>