Lauren Janine Donovan

All Publications

• Schwann cell-secreted PGE2 promotes sensory neuron excitability during development. Cell Kantarci, H., Elvira, P. D., Thottumkara, A. P., O'Connell, E. M., Iyer, M., Donovan, L. J., Dugan, M. Q., Ambiel, N., Granados, A., Zeng, H., Saw, N. L., Brosius Lutz, A., Sloan, S. A., Gray, E. E., Tran, K. V., Vichare, A., Yeh, A. K., Münch, A. E., Huber, M., Agrawal, A., Morri, M., Zhong, H., Shamloo, M., Anderson, T. A., Tawfik, V. L., Du Bois, J., Zuchero, J. B. 2024

  Abstract

  Electrical excitability-the ability to fire and propagate action potentials-is a signature feature of neurons. How neurons become excitable during development and whether excitability is an intrinsic property of neurons remain unclear. Here, we demonstrate that Schwann cells, the most abundant glia in the peripheral nervous system, promote somatosensory neuron excitability during development. We find that Schwann cells secrete prostaglandin E2, which is necessary and sufficient to induce developing somatosensory neurons to express normal levels of genes required for neuronal function, including voltage-gated sodium channels, and to fire action potential trains. Inactivating this signaling pathway in Schwann cells impairs somatosensory neuron maturation, causing multimodal sensory defects that persist into adulthood. Collectively, our studies uncover a neurodevelopmental role for prostaglandin E2 distinct from its established role in inflammation, revealing a cell non-autonomous mechanism by which glia regulate neuronal excitability to enable the development of normal sensory functions.

  View details for DOI 10.1016/j.cell.2024.07.033

  View details for PubMedID 39142281

• Repopulated spinal cord microglia exhibit a unique transcriptome and contribute to pain resolution. Cell reports Donovan, L. J., Bridges, C. M., Nippert, A. R., Wang, M., Wu, S., Forman, T. E., Haight, E. S., Huck, N. A., Bond, S. F., Jordan, C. E., Gardner, A. M., Nair, R. V., Tawfik, V. L. 2024; 43 (2): 113683

  Abstract

  Microglia are implicated as primarily detrimental in pain models; however, they exist across a continuum of states that contribute to homeostasis or pathology depending on timing and context. To clarify the specific contribution of microglia to pain progression, we take advantage of a temporally controlled transgenic approach to transiently deplete microglia. Unexpectedly, we observe complete resolution of pain coinciding with microglial repopulation rather than depletion. We find that repopulated mouse spinal cord microglia are morphologically distinct from control microglia and exhibit a unique transcriptome. Repopulated microglia from males and females express overlapping networks of genes related to phagocytosis and response to stress. We intersect the identified mouse genes with a single-nuclei microglial dataset from human spinal cord to identify human-relevant genes that may ultimately promote pain resolution after injury. This work presents a comprehensive approach to gene discovery in pain and provides datasets for the development of future microglial-targeted therapeutics.

  View details for DOI 10.1016/j.celrep.2024.113683

  View details for PubMedID 38261512

• Newly Repopulated Spinal Cord Microglia Exhibit A Unique Transcriptome And Coincide With Sex-Independent Pain Resolution Bridges, C. M., Donovan, L. J., Nippert, A. R., Wang, M., Wu, S., Forman, T. E., Haight, E. S., Huck, N. A., Jordan, C. E., Gardner, A. S., Nair, R. V., Tawfik, V. L. CHURCHILL LIVINGSTONE. 2023: 5-6

  View details for Web of Science ID 000995432100014

• Nociceptor Senescence Following Painful Peripheral Nerve Injury In Young And Aged Mice Donovan, L. J., Lopez, A., Jordan, C. E., Gardner, A. S., Tawfik, V. L. CHURCHILL LIVINGSTONE. 2023: 71-72

  View details for Web of Science ID 000995432100192

• Sex-distinct microglial activation and myeloid cell infiltration in the spinal cord after painful peripheral injury. Neurobiology of pain (Cambridge, Mass.) Huck, N. A., Donovan, L. J., Shen, H., Jordan, C. E., Muwanga, G. P., Bridges, C. M., Forman, T. E., Cordonnier, S. A., Haight, E. S., Dale-Huang, F., Takemura, Y., Tawfik, V. L. 2022; 12: 100106

  Abstract

  Chronic pain is a common and often debilitating problem that affects 100 million Americans. A better understanding of pain's molecular mechanisms is necessary for developing safe and effective therapeutics. Microglial activation has been implicated as a mediator of chronic pain in numerous preclinical studies; unfortunately, translational efforts using known glial modulators have largely failed, perhaps at least in part due to poor specificity of the compounds pursued, or an incomplete understanding of microglial reactivity. In order to achieve a more granular understanding of the role of microglia in chronic pain as a means of optimizing translational efforts, we utilized a clinically-informed mouse model of complex regional pain syndrome (CRPS), and monitored microglial activation throughout pain progression. We discovered that while both males and females exhibit spinal cord microglial activation as evidenced by increases in Iba1, activation is attenuated and delayed in females. We further evaluated the expression of the newly identified microglia-specific marker, TMEM119, and identified two distinct populations in the spinal cord parenchyma after peripheral injury: TMEM119+microglia and TMEM119- infiltrating myeloid lineage cells, which are comprised of Ly6G+neutrophils and Ly6G- macrophages/monocytes. Neurons are sensitized by inflammatory mediators released in the CNS after injury; however, the cellular source of these cytokines remains somewhat unclear. Using multiplex in situ hybridization in combination with immunohistochemistry, we demonstrate that spinal cord TMEM119+microglia are the cellular source of cytokines IL6 and IL1beta after peripheral injury. Taken together, these data have important implications for translational studies: 1) microglia remain a viable analgesic target for males and females, so long as duration after injury is considered; 2) the analgesic properties of microglial modulators are likely at least in part related to their suppression of microglial-released cytokines, and 3) a limited number of neutrophils and macrophages/monocytes infiltrate the spinal cord after peripheral injury but have unknown impact on pain persistence or resolution. Further studies to uncover glial-targeted therapeutic interventions will need to consider sex, timing after injury, and the exact target population of interest to have the specificity necessary for translation.

  View details for DOI 10.1016/j.ynpai.2022.100106

  View details for PubMedID 36531615