We are interested in synapse formation and the role of nicotinic cholinergic signaling in the developing nervous system. We have previously identified components required to build nicotinic synapses on neurons and are now examining their contributions to synaptic function and downstream signaling. A major new direction in the lab is the analysis of how nicotinic signaling contributes to neuronal development and innervation more globally. We have made the surprising discovery that nicotinic input helps drive the conversion of GABAergic transmission from excitation to inhibition during development in much of the nervous system. It appears to play a similar role for newborn neurons in the adult hippocampus, affecting their fate and dendritic fields. Moreover, we find that nicotinic activity appears to enhance glutamate synapse formation directly in the hippocampus. These results suggest profound effects of endogenous nicotinic signaling in neuronal development and integration into circuits.
Our laboratory takes a multidisciplinary approach. We want to identify the molecular players at nicotinic synapses and understand how they work. We also want to understand how these components interact in more complex ways to regulate circuit construction and system output. To do this, we combine molecular, physiological, imaging, and biochemical techniques, applying them both in culture and in vivo. Recent collaborations have also incorporated computational and ultrastructural analyses. And we are using viral constructs and mutant mice to manipulate nicotinic components in vivo during development and in the adult. This latter approach is enabling us to examine, for example, newborn neurons in adult hippocampus and evaluate nicotinic contributions to stem cell fate.
It is an exciting time to be investigating nicotinic signaling in the CNS. At the behavioral level nicotinic cholinergic activity has been implicated in a broad array of phenomena including cognition, memory formation, and arousal. It is also associated with numerous pathologies including Alzheimer's disease, schizophrenia, and addiction. These physiological consequences of nicotinic activity offer intriguing windows into higher brain function while at the same time suggesting biomedical applications. How the known cellular events of nicotinic signaling relate to higher order function remains a mystery and presents an ongoing challenge. Molecular tools are now in place to make major advances in these areas.
Gomez-Varela D, Schmidt M, Schoellerman J, Peters E, Berg DK (2012) PMCA2 via PSD-95 controls signaling by α7-containing nicotinic acetylcholine receptors on aspiny neurons. J. Neurosci., in press.
Lozada AF, Wang X, Gounko NV, Massey KA, Duan J, Liu Z, Berg DK (2012) Glutamatergic synapse formation is promoted by α7-containing nicotinic acetylcholine receptors. J. Neurosci., in press.
Lozada AF, Wang X, Gounko NV, Massey KA, Duan J, Liu Z, Berg DK (2012) Induction of dendritic spines by β2-containing nicotinic receptors. J. Neurosci., in press.
Campbell NR, Fernandes CC, Halff AW, Berg DK (2010) Endogenous signaling through α7-containing nicotinic receptors promotes maturation and integration of adultborn neurons in the hippocampus. J. Neurosci. 30: 8734-8744. (PMID: 20592195; PMCID: PMC2905643)
Fernandes CC, Berg DK, Gomez-Varela D (2010) Lateral mobility of nicotinic acetylcholine receptors on neurons is determined by receptor composition, local domain, and cell type. J. Neurosci. 30: 8841-8851 (and Journal cover). (PMID: 20592206; PMCID: PMC2913715)
Neff RA, Conroy WG, Schoellerman JD, Berg DK (2009) Synchronous and asynchronous transmitter release at nicotinic synapses are differentially regulated by postsynaptic PSD-95 proteins. J. Neurosci. 29: 15770-15779. (PMID: 200116093)
Zhang, J., and Berg, D.K. (2007). Reversible inhibition of GABAA receptors by α7-containing nicotinic receptors on vertebrate postsynaptic neurons. J. Physiol. (Lond.), 579: 753-763.
Conroy, W.G., Nai, Q., Ross, B., Naughton, G., and Berg, D.K. (2007). Postsynaptic neuroligin enhances presynaptic inputs at neuronal nicotinic synapses. Dev. Biol. 307: 79-91.
Liu, Z., Neff, R.A., and Berg, D.K. (2006). Sequential interplay of nicotinic and GABAergic signaling guides neuronal development. Science 314: 1610-1613.
Coggan, J.S., Bartol, T.M., Esquenazi, E., Stiles, J.R., Lamont, S., Martone, M.E., Berg D.K., Ellisman, M.H., and Sejnowski, T.J. (2005). Ectopic neurotransmitter release at a neuronal synapse. Science 309: 446-451.
Liu, Z., Tearle, A.W., Nai, Q., and Berg, D.K. (2005). Rapid activity-driven SNARE-dependent trafficking of nicotinic receptors. J. Neurosci. 25: 1159-1168.
Conroy, W.G., Liu, Z., Nai, Q., Coggan, J.S., and Berg, D.K. (2003). PDZ-containing proteins provide a functional postsynaptic scaffold for nicotinic receptors in neurons. Neuron 38: 759-771.
Kawai, H., Zago, W., and Berg, D.K. (2002). Nicotinic α7 receptor clusters on hippocampal GABAergic neurons: regulation by synaptic activity and neurotrophins. J. Neurosci. 22: 7903-7912.
Shoop, R.D., Esquenazi, E., Yamada, N., Ellisman, M.H., and Berg, D.K. (2002). Ultrastructure of a somatic spine mat for nicotinic signaling in neurons. J. Neurosci. 22: 748-756.
Chang, K., and Berg, D.K. (2001). Voltage-gated channels block nicotinic regulation of CREB phosphorylation and gene expression in neurons. Neuron 32: 855-865.
Liu, Q.-s., Kawai, H., and Berg, D.K. (2001). β-Amyloid peptide blocks the response of a7-containing nicotinic receptors on hippocampal neurons. Proc. Natl. Acad. Sci. (USA) 98: 4734-4739.
Darwin Berg received his Ph.D. from the University of California, Berkeley, and carried out postdoctoral studies at Harvard Medical School. He is the recipient of a Guggenheim Fellowship and a Javits Neuroscience Investigator Award. Dr. Berg has served as Chair of the UCSD Dept of Biology and Chair of the Graduate Program in Biological Sciences. Currently he is Chair of the Neurobiology Section. He also served previously as a Councilor of the Society for Neuroscience and is currently Treasurer for the Society.