Nervous system development; glia, microglia, caspase
Massachusetts Institute of Technology, University of Washington
My research addresses the development of the auditory brainstem nuclei and their synaptic connections. One set of studies addresses the embryonic origins of the cells that make up the nuclei. Our fate mapping study showed that precursors for two avian nuclei, N. magnocellularis (NM) and N. laminaris (NL) are specified early in development and arise from distinct locations within the hindbrain. These results suggest that NM and NL precursors follow distinct migratory pathways. Current studies are aimed at understanding how these distinct migratory pathways are established.
A second set of studies addresses the molecular mechanisms underlying the formation of precise connections in the auditory system. The projection from NM to NL is binaurally segregated. This arrangement facilitates sound localization in the mature auditory system. In addition, the auditory pathways preserve the tonotopic arrangement of best frequencies from the cochlea. We are investigating the molecular mechanisms underlying the formation of these precise projections.
Finally, we are studying the potential relationship between mechanisms of development and mechanisms of plasticity when connections in the auditory brainstem are altered following deafferentation. Do the same molecules serve to establish appropriate connections in both cases? How does neuronal activity influence the expression of these molecules? These studies will provide insight into brain reorganization, and may contribute to our understanding of how the brain repairs itself in response to injury.
Jayashankar V, Selwan E, Hancock SE, Verlande A, Goodson MO, Eckenstein KH, Milinkeviciute G, Hoover BM, Chen B, Fleischman AG, Cramer KS, Hanessian S, Masri S, Turner N, and Edinger AL. (2021) Drug-like sphingolipid SH-BC-893 opposes ceramide-induced mitochondrial fission and corrects diet-induced obesity. EMBO Mol Med Jul 7:e13086. doi: 10.15252/emmm.202013086.
Milinkeviute G, Chokr SM, and Cramer KS (2021) CX3CR1 mutation alters synaptic and astrocytic protein expression, topographic gradients, and response latencies in the auditory brainstem. J Comp Neurol. Apr 2. doi: 10.1002/cne.25150.
Milinkeviute G, Chokr SM, and Cramer KS (2021) Auditory brainstem deficits from early treatment with a CSF1R inhibitor largely recover with microglial repopulation. eNeuro Mar 22;8(2):ENEURO.0318-20.2021. doi: 10.1523/ENEURO.0318-20.2021.
Weghorst F, Mirzakhanyan Y, Samimi K, Dhillon M, Barzik M, Cunningham LL, Gershon PD, and Cramer KS (2020) Caspase-3 cleaves extracellular vesicle proteins during auditory brainstem development. Front Cell Neurosci. 12;14:573345. doi: 10.3389/fncel.2020.573345
McCullagh EA, Rotschafer SE, Auerbach BD, Klug A, Kaczmarek LK, Cramer KS, Kulesza RJ, Razak KA, Lovelace JW, Lu Y, Koch U, and Wang Y (2020) Mechanisms underlying auditory hypersensitivity in fragile X syndrome. FASEB Journal, Feb 10. doi: 10.1096/fj.201902435R
Milinkeviciute G and Cramer KS. (2020) Development of the ascending auditory pathway. In B. Grothe and B. Fritzch (eds), The Senses; Audition. Elsevier.
Milinkeviute G, Henningfield CM, Muniak MA, Chokr SM, Green KN, and Cramer KS (2019). Microglia regulate pruning of specialized synapses in the auditory brainstem. Front. Neural Circuits 13:55. doi: 10.3389/fncir.2019.00055
Weghorst FP and Cramer KS (2019) The evolution of hearing and balance. Elife. 2019 Feb 8;8. pii: e44567. doi: 10.7554/eLife.44567.
Milinkeviciute G and Cramer KS. (2018) Glial cells in the auditory brainstem. In K. Kandler (ed), Neuroscience Handbook Series: The Auditory Brainstem: Organization, Function, and Plasticity. Oxford University Press.
Rotschafer SE and Cramer KS (2017) Developmental emergence of phenotypes in the auditory brainstem nuclei of Fmr1 knockout mice. eNeuro. ENEURO.0264-17.2017. doi: 10.1523/ENEURO.0264-17.2017. eCollection 2017 Nov-Dec.
Cramer KS and Coffin AB. (2017) Auditory system development: a tribute to Edwin W Rubel. In K. Cramer et al. (eds.), Auditory Development and Plasticity, Springer Handbook of Auditory Research 64.
Rotschafer SE, Allen-Sharpley MR and Cramer KS (2016) Axonal cleaved caspase-3 regulates axon targeting and morphogenesis in the developing auditory brainstem. Front. Neural Circuits 10:84. doi: 10.3389/fncir.2016.00084
Cramer KS and Rubel EW (2016) Glial cell contributions to auditory brainstem development. Front. Neural Circuits. 10:83. doi: 10.3389/fncir.2016.00083
Cramer KS and Miko IJ (2016) Eph-ephrin signaling in nervous system development. F1000Research 2016, 5(F1000 Faculty Rev):413 (doi: 10.12688/f1000research.7417.1)
Abdul-Latif ML, Salazar JA, Marshak S, Dinh ML, Cramer KS (2015). Ephrin-A2 and ephrin-A5 guide contralateral targeting but not topographic mapping of ventral cochlear nucleus axons. Neural Dev. 2015 Dec 15;10:27. doi: 10.1186/s13064-015-0054-6.
Rotschafer SE, Marshak S, and Cramer KS (2015). Deletion of Fmr1 alters function and synaptic inputs in the auditory brainstem. PLoS One, 13;10(2):e0117266. doi: 10.1371/journal.pone.0117266.
Dinh ML, Koppel SJ, Korn MJ, and Cramer KS. (2014) Distribution of glial cells in the auditory brainstem: Normal development and effects of unilateral lesion. Neuroscience (278C): 237-252.
Cramer KS and Gabriele ML. (2014) Axon guidance in the auditory system: Multiple functions of Eph receptors. Neuroscience (277C): 152-162.
Allen-Sharpley MR, Tjia M, and Cramer KS. (2013) Differential roles for EphA and EphB signaling in segregation and patterning of central vestibulocochlear nerve projections. PLoS One, Oct 10;8(10):e78658. doi: 10.1371/journal.pone.0078658.
Allen-Sharpley MR, Tjia M, and Cramer KS. (2013) Selective tracing of auditory fibers in the avian embryonic vestibulocochlear nerve. J. Vis. Exp. (73), e50305, doi:10.3791/50305.
Nakamura PA and Cramer KS. (2013) EphB2 signaling reulates lesion-induces axon sprouting but not critical period length in the postnatal auditory brainstem. Neural Dev. Feb 5;8:2. doi: 10.1186/1749-8104-8-2. PMCID: PMC3575227
Nakamura PA, Hsieh CY, and Cramer KS. (2012) EphB signaling regulates target innervation in the developing and deafferented auditory brainstem. Dev. Neurobiol. 72:1243-55. PMCID: PMC3418463
Allen-Sharpley MR and Cramer KS. (2012) Coordinated Eph-ephrin signaling guides migration and axon targeting in the avian auditory system. Neural Dev. Aug 21;7:29. doi: 10.1186/1749-8104-7-29.
Korn MJ, Koppel SJ, Li LH, Mehta D, Mehta SB, Seidl AH, Cramer KS. (2011)
Astrocyte-secreted factors modulate the developmental distribution of inhibitory
synapses in nucleus laminaris of the avian auditory brainstem. J Comp Neurol.
2011 Oct 20. doi: 10.1002/cne.22786. [Epub ahead of print] PubMed PMID: 22020566.
Korn MJ, Koppel SJ, Cramer KS. Astrocyte-secreted factors modulate a gradient of primary dendritic arbors in nucleus laminaris of the avian auditory brainstem. PLoS One. 2011;6(11):e27383. Epub 2011 Nov 7. PubMed PMID: 22087304; PubMed
Central PMCID: PMC3210166.
Intskirveli I, Metherate R, Cramer KS. Null mutations in EphB receptors
decrease sharpness of frequency tuning in primary auditory cortex. PLoS One.
2011;6(10):e26192. Epub 2011 Oct 12. PubMed PMID: 22022561; PubMed Central PMCID:
Nakamura PA and Cramer KS. (2010) Formation and maturation of the calyx of Held. Hearing Research, 276:70-78
Hsieh CY, Nakamura PA, Luks SO, Miko IJ, Henkemeyer M, and Cramer KS. (2010) Ephrin-B reverse signaling is required for formation of strictly contralateral auditory brainstem pathways. J. Neurosci. 30:9840-9849.
Korn MJ and Cramer KS. (2008) The distribution of glial associated proteins in the developing chick auditory brainstem. Developmental Neurobiology 68:1093-1106.
Miko IJ, Henkemeyer M, and Cramer KS (2008) Auditory brainstem responses are impaired in EphA4 and ephrin-B2 deficient mice. Hearing Research, 235:39-46.
Miko IJ, Nakamura PA, Henkemeyer M, and Cramer KS (2007) Auditory brainstem neural activation patterns are altered in EphA4- and ephrin-B2 deficient mice. J. Comp. Neurol., 505: 669-681.
Hsieh CY, Hong CT, and Cramer KS (2007) Deletion of EphA4 enhances deafferentation-induced ipsilateral sprouting in auditory brainstem projections. J. Comp. Neurol., 504: 508-518.
Korn MJ and Cramer KS. (2007) Placing growth factor-coated beads on early stage chicken embryos. J Vis Exp. (8) 307.
Huffman KJ and Cramer KS (2007) EphA4 misexpression alters tonotopic projections in the auditory brainstem. Developmental Neurobiology 67:1655-1668.
Korn MJ and Cramer KS. (2007) Windowing chicken eggs for developmental studies. J Vis Exp. (8) 306.
Hsieh CY and Cramer KS. (2006) Deafferentation induces novel axonal projections in the auditory brainstem after hearing onset. J. Comp. Neurol., 497:589-599.
Cramer KS, Cerretti DP, and Siddiqui SA. (2006) EphB2 regulates axonal growth at the midline in the developing auditory brainstem. Developmental Biology 295:76-89.
Cramer KS. (2005) Eph proteins and the assembly of auditory circuits. Hearing Research, 206:42-51.
Siddiqui SA and Cramer KS. (2005) Differential expression of Eph receptors and ephrins in the cochlear ganglion and eighth cranial nerve of the chick embryo. J. Comp. Neurol., 482:309-19.
Burger RM, Cramer KS, Pfeiffer JD, Rubel EW. (2005) The avian superior olivary nucleus provides divergent inhibitory input to parallel auditory pathways. J. Comp. Neurol., 481:6-18.
Person AL, Cerretti DP, Pasquale EP, Rubel EW, and Cramer KS. (2004) Tonotopic gradients of Eph family proteins in the chick nucleus laminaris during synaptogenesis. J. Neurobiol. 60:28-39.
Cramer KS, Bermingham-McDonogh OM, Krull CE, and Rubel EW (2004) EphA4 signaling promotes axon segregation in the developing auditory system. Developmental Biology 269:26-35.
Eberhart J, Barr J, O’Connell S, Flagg A, Swartz ME, Cramer KS, Tosney, K, Pasquale EB, and Krull CE. (2004) Ephrin-A5 exerts positive or inhibitory effects on distinct subsets of EphA4-positive motor neurons. J. Neurosci. 24:1070-1078.
Cramer KS, Karam SD, Bothwell M, Cerretti DP, Pasquale EP, and Rubel EW (2002) Expression of EphB receptors and ephrinB ligands in the developing chick auditory brainstem. J. Comp. Neurol., 452: 51-64.
Rubel EW and Cramer KS. (2002) Choosing axonal real estate: location, location, location. Commentary, J. Comp. Neurol. 448: 1-5.
Cramer KS, Rosenberger MH, Frost DM, Cochran SL, Pasquale EB, and Rubel EW. (2000) Developmental regulation of EphA4 expression in the chick auditory brainstem. J. Comp. Neurol. 426: 270-278.
Cramer KS, Fraser SE, and Rubel, EW. (2000) Embryonic origins of auditory brainstem nuclei in the chick hindbrain. Developmental Biology 224: 138-151.
Hahm J, Cramer KS and Sur M (1999) Pattern formation by retinal afferents in the ferret lateral geniculate nucleus: Developmental segregation and the role of N-methyl-D-aspartate receptors. J. Comp. Neurol. 411: 327-345.
Cramer KS and Sur M. (1999) The neuronal form of nitric oxide synthase is required for sublaminar segregation in the ferret lateral geniculate nucleus. Dev. Brain Res. 116: 79-86.
Angelucci A, Bricolo E, Clasca F, Cramer KS, and Sur M (1997) Experimentally induced retinal projections to the ferret auditory thalamus: Development of clustered eye-specific patterns in a novel target. J. Neurosci. 17: 2040-2055.
Cramer KS and Sur M (1997) Blockade of afferent impulse activity disrupts ON/OFF sublamination in the ferret lateral geniculate nucleus. Dev. Brain Res. 98: 287-290.
Cramer KS, Angelucci A, Hahm J, Bogdanov MB, and Sur M (1996) A role for nitric oxide in the development of the ferret retinogeniculate projection. J. Neurosci. 16: 7995-8004.
Cramer KS and Sur M (1995) Activity-dependent remodeling of connections in the mammalian visual system. Current Opinion in Neurobiology 5: 106-111.
NIH NIDCD R01 Glial Influences on Auditory Brainstem Development
Society for Neuroscience
Association for Research in Otolaryngology
Neurobiology and Behavior
Interdepartmental Neuroscience Program
Center for Hearing Research
Center for the Neurobiology of Learning and Memory
Center for Autism Research and Treatment