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Nicholas Spitzer

Research

The brain is capable of a rich variety of forms of plasticity, changing its structure and function in response to changes in the environment. We are studying neurotransmitter switching, a newly appreciated form of neuroplasticity in which neurons change the transmitters that they make and release in response to sustained sensory or motor activity. Transmitter identity often switches from excitatory to inhibitory or vice versa, with matching changes in postsynaptic receptors, both in the developing amphibian nervous system and in the adult rodent brain. Perhaps unsurprisingly, the reversal of the sign of synaptic transmission is accompanied by changes in the animals' behavior. Restoration of transmitter identity by environmental stimulation or with viral vectors restores normal behavior.

Our recent studies have demonstrated the roles of sensory and motor stimuli and direct manipulations of activity in neurotransmitter switching in the developing Xenopus hypothalamus, brainstem, and accessory olfactory bulb (Dulcis & Spitzer, 2008; Demarque & Spitzer, 2010; Dulcis et al., 2017) and in the adult rat hypothalamus and midbrain (Dulcis et al. 2013; Meng et al., 2018; Li & Spitzer, 2020). We have found that motor activity drives neurotransmitter switching in the adult mouse hippocampus that appears to regulate episodic memory. We have discovered neurotransmitter switching in the medial prefrontal cortex, dorsal raphe and prelimbic cortex that is associated with changes in behavior in stress-dependent mouse models of autism spectrum disorders, PTSD, and responses to drugs of abuse.

Our work is now focused on understanding the cues that stimulate neurotransmitter switching in the developing and adult mouse brain, the prevalence and forms of this plasticity, and its functions. We want to learn the molecular mechanisms that regulate neurotransmitter switching and the mechanisms by which the appropriate, matching transmitter receptors are expressed on postsynaptic cells. We are investigating neurotransmitter switching in response to pleasurable stimuli such as exercise and to aversive stimuli such as stress and drug abuse. There are many fascinating questions to address.

Select Publications

  • Pratelli, M., Hakimi, A.M., Thaker, A., Jang, H., Li, H., Godavarthi S.K., Lim, B.K., Spitzer, N.C. (2024) Drug-induced change in transmitter identity is a shared mechanism generating cognitive deficits. Nat Commun 15: 8260.
  • Godavarthi, S.K., Li, H., Pratelli, M., Spitzer, N.C. (2024) Embryonic exposure to environmental factors drives transmitter switching in the neonatal mouse cortex causing autistic-like adult behavior. Proc Natl Acad Sci U S A 121: e2406928121.
  • Godavarthi, S.K, Hiramoto, M., Ignatyev, Y., Levin, J.B., Li, H., Pratelli, M., Borchardt, J., Czajkowski, C., Borodinsky, L.N., Sweeney, L., Cline, H.T., Spitzer, N.C. (2024) Postsynaptic receptors regulate presynaptic transmitter stability through transsynaptic bridges. Proc Natl Acad Sci U S A 121: e2318041121.
  • Li, H., Jiang W., Ling, Li, Pratelli, M., Chen, C., Gupta, V., Godavarthi, S.K., Spitzer, N.C. (2024) Generalized fear after acute stress is caused by change in neuronal cotransmitter identity. Science 383: 1252–1259.
  • Li, H., Pratelli, M., Godavarthi, S., Zambetti, S., Spitzer, N.C. (2020) Decoding neurotransmitter switching: the road forward. J. Neurosci. 40: 4078-4089.
  • Li, H., Spitzer, N.C. (2020) Exercise enhances motor skill learning by neurotransmitter switching in the adult midbrain. Nat Commun 11: 2195.
  • Hammond-Weinberger, D.R., Wang, Y., Glavis-Bloom, A., Spitzer, N.C. (2020) Mechanism for neurotransmitter-receptor matching. Proc Natl Acad Sci U S A., 17: 4368-4374.
  • Pritchard, R., Chen, H., Romoli, B., Spitzer, N.C., Dulcis, D. (2020) Photoperiod-induced neurotransmitter plasticity declines with aging: an epigenetic regulation? J. Comp. Neurol., 528: 199–210.
  • Meng, D., Li, H.Q., Deisseroth, K., Leutgeb, S., Spitzer, N.C. (2018) Neuronal activity regulates neurotransmitter switching in the adult brain following light-induced stress. Proc Natl Acad Sci U S A 115: 5064-5071.
  • Spitzer, N.C. (2017) Neurotransmitter switching in the developing and adult brain. Ann. Rev. Neurosci. 40: 1-19.
  • Li, H., Pratelli, M., Godavarthi, S., Zambetti, S., Spitzer, N.C. (2020) Decoding neurotransmitter switching: the road forward. J. Neurosci. 40: 4078-4089.
  • Li, H., Spitzer, N.C. (2020) Exercise enhances motor skill learning by neurotransmitter switching in the adult midbrain. Nat Commun 11: 2195.
  • Hammond-Weinberger, D.R., Wang, Y., Glavis-Bloom, A., Spitzer, N.C. (2020) Mechanism for neurotransmitter-receptor matching. Proc Natl Acad Sci U S A., 17: 4368-4374.
  • Pritchard, R., Chen, H., Romoli, B., Spitzer, N.C., Dulcis, D. (2020) Photoperiod-induced neurotransmitter plasticity declines with aging: an epigenetic regulation? J. Comp. Neurol., 528: 199–210.
  • Meng, D., Li, H.Q., Deisseroth, K., Leutgeb, S., Spitzer, N.C. (2018) Neuronal activity regulates neurotransmitter switching in the adult brain following light-induced stress. Proc Natl Acad Sci U S A. 115: 5064-5071.
  • Spitzer, N.C. (2017) Neurotransmitter switching in the developing and adult brain. Ann. Rev. Neurosci. 40: 1-19.
  • Dulcis, D., Lippi, G., Stark, C.J., Do, L.H., Berg, D.K., Spitzer, N.C. (2017) Neurotransmitter switching regulated by miRNAs controls changes in social preference. Neuron. 95: 1319-1333.
  • Aumann, T.D., Raabus, M., Tomas, D., Prijanto, A., Churilov, L., Spitzer, N.C., Horne, M.K. (2016) Differences in number of midbrain dopamine neurons associated with summer and winter photoperiods in humans. PLoS One 11: e0158847.
  • Spitzer, N.C. (2015) Neurotransmitter switching? No surprise. Neuron 86: 1131-1144.
  • Güemez-Gamboa, A. Xu, L., Meng, D., Spitzer, N.C. (2014) Non-cell-autonomous mechanism of activity-dependent neurotransmitter switching. Neuron 82: 1004-1016.
  • Dulcis, D., Jamshidi, P., Leutgeb, S. and Spitzer, N.C. (2013) Neurotransmitter switching in the adult brain regulates behavior. Science 340: 449-453.
  • Plazas, P.V., Nicol, X. and Spitzer, N.C. (2013) Activity-dependent competition regulates motor neuron axon pathfinding via PlexinA3. Proc. Nat. Acad. Sci. USA. 110: 1524-1529.
  • Spitzer, N.C. (2012) Activity-dependent neurotransmitter respecification. Nature Reviews Neurosci. 13: 94-106.
  • Dulcis, D. and Spitzer, N.C. (2012) Reserve pool neuron transmitter respecification: novel neuroplasticity. Dev. Neurobiol. 72: 465-474.
  • Demarque, M. and Spitzer, N.C. (2012) Neurotransmitter phenotype plasticity: an unexpected mechanism in the toolbox of network activity homeostasis. Dev. Neurobiol. 72: 22-32.
  • Nicol, X., Hong, K.P. and Spitzer, N.C. (2011) Spatial and temporal second messenger codes for growth cone turning. Proc. Nat. Acad. Sci. USA. 108: 13776-13781.
  • Velázquez-Ulloa, N.A., Spitzer, N.C. and Dulcis, D. (2011) Context-dependent dopamine specification by calcium activity across the central nervous system. J. Neurosci. 31: 78-88.
  • Demarque, M. and Spitzer, N.C. (2010) Activity-dependent expression of Lmx1b regulates specification of serotonergic neurons modulating swimming behavior. Neuron 67: 321-334.
  • Marek, K.W., Kurtz, L.M. and Spitzer, N.C. (2010) cJun integrates calcium spike activity and tlx3 expression to regulate neurotransmitter specification. Nature Neurosci. 13: 944-950.
  • Xiao, Q., Xu, L. and Spitzer, N.C. (2010) Muscle-dependent regulation of neurotransmitter specification and embryonic neuronal calcium spike activity. J. Neurosci. 30: 5792-5801.
  • Chang, L.W. and Spitzer, N.C. (2009) Spontaneous calcium spike activity in embryonic spinal neurons is regulated by developmental expression of the Na+, K+-ATPase β3 subunit. J. Neurosci. 29: 7877-7885.
  • Dulcis, D. and Spitzer, N.C. (2008) Illumination controls dopaminergic differentiation regulating behavior. Nature 456: 195-201.
  • Root, C.M., Velazquez-Ulloa, N.A., Monsalve, G.C., Minakova, E. and Spitzer, N.C. (2008). Embryonically expressed GABA and glutamate drive electrical activity regulating neurotransmitter specification. J. Neurosci. 28: 4777-4784.
  • Sann, S.B., Xu, L., Nishimune, H., Sanes, J.R. and Spitzer, N.C. (2008). Neurite outgrowth and in vivo sensory innervation mediated by a CaV2.2-laminin beta-2 stop signal. J. Neurosci. 28: 2366-2374.
  • Borodinsky, L.N. and Spitzer, N.C. (2007). Activity-dependent neurotransmitter-receptor matching at the neuromuscular junction. Proc. Natl. Acad. Sci. 104: 335-340.
  • Spitzer, N.C. (2006). Electrical activity in early neuronal development. Nature 444: 707-712.
  • Conklin, M.W., Lin, M.S. and Spitzer, N.C. (2005). Local calcium transients contribute to disappearance of pFAK, focal complex removal and deadhesion of neuronal growth cones and fibroblasts. Dev. Biol. 287: 201-212.
  • Borodinsky, L.N., Root, C.M., Cronin, J.A., Sann, S.B., Gu, X. and Spitzer, N.C. (2004). Activity-dependent homeostatic specification of transmitter expression in embryonic neurons. Nature 429: 523-530.
  • Gorbunova, Y.V. and Spitzer, N.C. (2002). Dynamic interactions of cAMP transients and spontaneous calcium spikes. Nature 418: 93-96.
  • Gomez, T.M., Robles, E., Poo, M. and Spitzer, N.C. (2001). Filipodial calcium transients promote substrate-dependent growth cone turning. Science 291: 1983-1987.

Biography

Nick Spitzer received his Ph.D. from Harvard University and was a postdoctoral fellow at Harvard and University College, London. He joined the faculty in 1972 and has been the recipient of a Sloan Fellowship, a Javits Neuroscience Investigator Award and a Guggenheim Fellowship. He was founding editor-in-chief of BrainFacts.org at the Society for Neuroscience and a founding co-director of the Kavli Institute for Brain and Mind at UC San Diego. He is a fellow of the American Association for the Advancement of Science and a member of the American Academy of Arts and Sciences and the National Academy of Sciences.

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