Sriram Sudarsanam

All Publications

• Cell-type-selective synaptogenesis during the development of layer 6 corticothalamic neuron connectivity in the mammalian neocortex. Cell reports Gutman-Wei, A. Y., Sudarsanam, S., Cabalinan, A. G., Shahid, N., Shi, A., Guzman-Clavel, L. E., Spindler-Krage, S. M., Agarwal, A., Kolodkin, A. L., Brown, S. P. 2026; 45 (1): 116792

  Abstract

  The function of the mammalian neocortex relies on the timing of axon extension and establishment of cell-type-biased patterns of excitatory synaptic connections. A subtype of excitatory neurons, layer 6 corticothalamic neurons (L6CThNs), ultimately exhibits a marked preference for synapsing onto parvalbumin-positive (PV) inhibitory interneurons over more common excitatory cells in layers 6 and 4 (L6, L4). We show that the intracortical axons of L6CThNs develop in phases, first elongating within L6, then pausing before extending translaminar branches into L4. Decreasing L6CThN excitability selectively enhances axon growth in L6 but not the later elaboration in L4. For both layers, we test whether preferential synaptogenesis onto rarer PV interneurons, or non-selective synapse formation followed by selective pruning, generates adult connectivity. We find that L6CThNs form functional AMPA-receptor-containing synapses preferentially onto PV interneurons. Silent L6CThN synapses are not detected. Our findings show that cell-type-biased synaptogenesis underlies the formation of functional cell-type-specific excitatory connections in the neocortex.

  View details for DOI 10.1016/j.celrep.2025.116792

  View details for PubMedID 41505254

• Mef2c Controls Postnatal Callosal Axon Targeting by Regulating Sensitivity to Ephrin Repulsion JOURNAL OF NEUROSCIENCE Sudarsanam, S., Guzman-Clavel, L. E., Dar, N., Ziak, J., Shahid, N., Jin, X. O., Kolodkin, A. L. 2025; 45 (21)

  Abstract

  Intracortical circuits, including long-range callosal projections, are crucial for information processing. The development of neuronal connectivity in the cerebral cortex is contingent on ordered emergence of neuronal classes followed by the formation of class-specific axon projections. However, the genetic determinants of intracortical axon targeting are still unclear. We find that the transcription factor myocyte enhancer factor 2-c (Mef2c) directs the development of somatosensory cortical (S1) Layer 4 and 5 identity in murine postmitotic pyramidal neurons during embryogenesis. During postnatal development, Mef2c expression shifts to Layer 2/3 callosal projection neurons (L2/3 CPNs). At this later developmental stage, we identify a novel function for Mef2c in contralateral homotopic domain targeting by S1-L2/3 CPN axons. We employ functional manipulation of EphrinA-EphA signaling in Mef2c mutant CPNs and demonstrate that Mef2c represses EphA6 to desensitize S1-L2/3 CPN axons to EphrinA5 repulsion at their contralateral targets. Our work uncovers dual roles for Mef2c in cortical development: regulation of laminar subtype specification during embryogenesis and axon targeting in postnatal callosal neurons.

  View details for DOI 10.1523/JNEUROSCI.0201-25.2025

  View details for Web of Science ID 001502225800003

  View details for PubMedID 40228894

  View details for PubMedCentralID PMC12096051

• Microtubule-binding protein MAP1B regulates interstitial axon branching of cortical neurons via the tubulin tyrosination cycle EMBO JOURNAL Ziak, J., Dorskind, J. M., Trigg, B., Sudarsanam, S., Jin, X. O., Hand, R. A., Kolodkin, A. L. 2024; 43 (7): 1214-1243

  Abstract

  Regulation of directed axon guidance and branching during development is essential for the generation of neuronal networks. However, the molecular mechanisms that underlie interstitial (or collateral) axon branching in the mammalian brain remain unresolved. Here, we investigate interstitial axon branching in vivo using an approach for precise labeling of layer 2/3 callosal projection neurons (CPNs). This method allows for quantitative analysis of axonal morphology at high acuity and also manipulation of gene expression in well-defined temporal windows. We find that the GSK3β serine/threonine kinase promotes interstitial axon branching in layer 2/3 CPNs by releasing MAP1B-mediated inhibition of axon branching. Further, we find that the tubulin tyrosination cycle is a key downstream component of GSK3β/MAP1B signaling. These data suggest a cell-autonomous molecular regulation of cortical neuron axon morphology, in which GSK3β can release a MAP1B-mediated brake on interstitial axon branching upstream of the posttranslational tubulin code.

  View details for DOI 10.1038/s44318-024-00050-3

  View details for Web of Science ID 001219749400005

  View details for PubMedID 38388748

  View details for PubMedCentralID PMC10987652

• Drebrin Regulates Collateral Axon Branching in Cortical Layer II/III Somatosensory Neurons JOURNAL OF NEUROSCIENCE Dorskind, J. M., Sudarsanam, S., Hand, R. A., Ziak, J., Amoah-Dankwah, M., Guzman-Clavel, L., Soto-Vargas, J., Kolodkin, A. L. 2023; 43 (46): 7745-7765

  Abstract

  Proper cortical lamination is essential for cognition, learning, and memory. Within the somatosensory cortex, pyramidal excitatory neurons elaborate axon collateral branches in a laminar-specific manner that dictates synaptic partners and overall circuit organization. Here, we leverage both male and female mouse models, single-cell labeling and imaging approaches to identify intrinsic regulators of laminar-specific collateral, also termed interstitial, axon branching. We developed new approaches for the robust, sparse, labeling of Layer II/III pyramidal neurons to obtain single-cell quantitative assessment of axon branch morphologies. We combined these approaches with cell-autonomous loss-of-function (LOF) and overexpression (OE) manipulations in an in vivo candidate screen to identify regulators of cortical neuron axon branch lamination. We identify a role for the cytoskeletal binding protein drebrin (Dbn1) in regulating Layer II/III cortical projection neuron (CPN) collateral axon branching in vitro LOF experiments show that Dbn1 is necessary to suppress the elongation of Layer II/III CPN collateral axon branches within Layer IV, where axon branching by Layer II/III CPNs is normally absent. Conversely, Dbn1 OE produces excess short axonal protrusions reminiscent of nascent axon collaterals that fail to elongate. Structure-function analyses implicate Dbn1S142 phosphorylation and Dbn1 protein domains known to mediate F-actin bundling and microtubule (MT) coupling as necessary for collateral branch initiation upon Dbn1 OE. Taken together, these results contribute to our understanding of the molecular mechanisms that regulate collateral axon branching in excitatory CPNs, a key process in the elaboration of neocortical circuit formation.SIGNIFICANCE STATEMENT Laminar-specific axon targeting is essential for cortical circuit formation. Here, we show that the cytoskeletal protein drebrin (Dbn1) regulates excitatory Layer II/III cortical projection neuron (CPN) collateral axon branching, lending insight into the molecular mechanisms that underlie neocortical laminar-specific innervation. To identify branching patterns of single cortical neurons in vivo, we have developed tools that allow us to obtain detailed images of individual CPN morphologies throughout postnatal development and to manipulate gene expression in these same neurons. Our results showing that Dbn1 regulates CPN interstitial axon branching both in vivo and in vitro may aid in our understanding of how aberrant cortical neuron morphology contributes to dysfunctions observed in autism spectrum disorder and epilepsy.

  View details for DOI 10.1523/JNEUROSCI.0553-23.2023

  View details for Web of Science ID 001148065300004

  View details for PubMedID 37798130

  View details for PubMedCentralID PMC10648559

• Cofilin regulates axon growth and branching of <i>Drosophila</i> γ-neurons JOURNAL OF CELL SCIENCE Sudarsanam, S., Yaniv, S., Meltzer, H., Schuldiner, O. 2020; 133 (8)

  View details for DOI 10.1242/jcs.232595

  View details for Web of Science ID 000534388600005