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Sharma, Nikhil

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Sharma

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Nikhil

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Sharma, Nikhil

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2012 - 20203

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Author's Publications: search.filters.isAuthorOfPublication.d6fa5d90-042d-437a-beea-125021b8214b

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    Bidirectional Perisomatic Inhibitory Plasticity of a Fos Neuronal Network
    (Springer Science and Business Media LLC, 2020-12-09) Yap, Ee-Lynn; Pettit, Noah L.; Davis, Christopher; Nagy, M. Aurel; Harmin, David; Golden, Emily; Dagliyan, Onur; Lin, Cindy; Rudolph, Stephanie; Sharma, Nikhil; Griffith, Eric C.; Harvey, Christopher D.; Greenberg, Michael
    Behavioral experiences activate the Fos transcription factor (TF) in sparse populations of neurons that are critical for encoding and recalling specific events1-3. However, there is limited understanding of the mechanisms by which experience drives circuit reorganization to establish a network of Fos-activated cells. It is also unknown if Fos is required in this process beyond serving as a marker of recent neural activity and, if so, which of its many gene targets underlie circuit reorganization. Here we demonstrate that when mice engage in spatial exploration of novel environments, perisomatic inhibition of Fos-expressing hippocampal CA1 pyramidal neurons by parvalbumin (PV)-interneurons (INs) is enhanced, while perisomatic inhibition by cholecystokinin (CCK)-INs is weakened. This bidirectional modulation of inhibition is abolished when the function of the Fos TF complex is disrupted. Single-cell RNA-sequencing, ribosome-associated mRNA profiling, and chromatin analyses, combined with electrophysiology, reveal that Fos activates the transcription of Scg2 (secretogranin II), a gene that encodes multiple distinct neuropeptides, to coordinate these changes in inhibition. As PV- and CCK-INs mediate distinct features of pyramidal cell activity4-6, the Scg2-dependent reorganization of inhibitory synaptic input might be predicted to affect network function in vivo. Consistent with this prediction, hippocampal gamma rhythms and pyramidal cell coupling to CA1 theta are significantly altered with loss of Scg2. These findings reveal an instructive role for Fos and Scg2 in establishing a network of Fos-activated neurons via the rewiring of local inhibition to form a selectively modulated state. The opposing plasticity mechanisms on distinct inhibitory pathways may support the consolidation of memories over time.
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    A Chemical Genetic Approach Reveals Distinct Mechanisms of EphB Signaling During Brain Development
    (2012) Soskis, Michael J.; Ho, Hsin-Yi Henry; Bloodgood, Brenda L.; Robichaux, Michael A.; Malik, Athar; Ataman, Bulent; Rubin, Alex A.; Zieg, Janine; Zhang, Chao; Shokat, Kevan M.; Sharma, Nikhil; Cowan, Christopher W.; Greenberg, Michael
    EphB receptor tyrosine kinases control multiple steps in nervous system development. However, it remains unclear whether EphBs regulate these different developmental processes directly or indirectly. In addition, as EphBs signal through multiple mechanisms, it has been challenging to define which signaling functions of EphBs regulate particular developmental events. To address these issues, we engineered triple knockin mice in which the kinase activity of three neuronally expressed EphBs can be rapidly, reversibly, and specifically blocked. Using these mice we demonstrate that the tyrosine kinase activity of EphBs is required for axon guidance in vivo. By contrast, EphB-mediated synaptogenesis occurs normally when the kinase activity of EphBs is inhibited suggesting that EphBs mediate synapse development by an EphB tyrosine kinase-independent mechanism. Taken together, these experiments reveal that EphBs control axon guidance and synaptogenesis by distinct mechanisms, and provide a new mouse model for dissecting EphB function in development and disease.
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    Activity Dependent Regulation of Inhibitory Circuitry
    (2015-10-02) Sharma, Nikhil; Dymecki, Susan; Pecot, Matthew; Gu, Chenghua; Tsai, Li-Heui
    Inhibition controls information flow through a neural circuit by modulating synaptic integration, restricting action potentials, and coordinating the activity of ensembles of neurons. These functions are mediated by a diverse array of inhibitory neuron subtypes that synapse on defined domains of a postsynaptic neuron. Activity-dependent transcription controls inhibitory synapse number and function, but how this transcription program affects the inhibitory inputs that form on distinct domains of a neuron remains unclear. We find that behaviorally-driven expression of the transcription factor NPAS4 orchestrates the redistribution of inhibitory synapses made onto a pyramidal neuron, simultaneously promoting inhibitory synapse formation onto the cell body while destabilizing inhibitory synapses formed on the dendrites. This rearrangement of inhibition across a neuron is mediated in part by the NPAS4 target gene brain derived neurotrophic factor (BDNF), which specifically regulates somatic inhibition. These findings suggest that sensory stimuli, by inducing NPAS4 and its target genes, differentially control spatial features of neuronal inhibition in a way that restricts the output of the neuron while creating a dendritic environment that is permissive for plasticity.