Mechanisms of synaptic plasticity: LTP, glutamate receptors and cell adhesion molecules; Cellular deficits underlying cognitive impairment in animal model sof cognitive impairment; Cellular mechanisms of neuronal vulnerability in brain aging;
Researcher of the Year (UCI)
Entrepreneur of the Year (UCI)
Our research is concerned with two aspects of memory storage: (1) the physiological and biochemical processes responsible for rapidly producing stable changes in synapses, and (2) the anatomy and physiology of circuitries responsible for encoding certain types of memory.
We have found that brief episodes of high-frequency electrical stimulation of axons in the hippocampus alter the structure and number of synaptic connections; subsequent work in different laboratories has shown that this effect is correlated with an increase in synaptic strength that lasts indefinitely. Physiological experiments strongly suggest that the stable potentiation is triggered by an influx of calcium occurring during the brief stimulation period, and this led us to search for a calcium-sensitive process that could produce localized anatomical reorganization. A candidate for this role has been identified. Brain cells contain an enzyme that, in the presence of calcium, causes the breakdown of structural proteins responsible for maintaining the shape and biochemical organization of synapses. We have hypothesized that intense synaptic activity stimulates this enzyme by increasing intracellular calcium and that the resultant breakdown and reorganization of synaptic structure produces more potent connections between neurons. One of the more intriguing aspects of this enzyme is that under some circumstances it appears to produce degeneration in nerves and muscles. This raises the possibility that excessive stimulation of the mechanism postulated to produce brain plasticity is also responsible for some instances of brain pathology, particularly those linked to aging. Several studies to explore this idea are underway.
Two recent sets of findings increase the likelihood that at least some aspects of the mechanism described above are involved in memory. First was the discovery that a naturally occurring brain rhythm is exceedingly potent in eliciting the stable synaptic potentiation effect. Beyond providing evidence that potentiation could occur during certain behaviors, the results suggest that particular patterns of brain activity are used not only to process information but to encode it as well. Second, pharmacological agents that block the potentiation effect or the calcium-sensitive enzyme selectively block certain types of memory storage in rats.
The discovery of a physiological/chemical process that is at least a plausible candidate for the memory mechanism prompted us to begin analyzing memory in terms of brain circuitries. Cognitive psychologists and neurologists have established that humans possess multiple memory systems and have uncovered some important clues about the brain regions involved in these.
Our studies sought to use rat brain networks that include these same areas and to find behavioral tasks that sample memory systems which correspond to those described for humans. These constraints led our search to the little-studied olfactory system in the rat brain. Thus far we have found that the relevant circuitries in rat brains bear a surprising resemblance to networks designed by theorists in the computer sciences to accomplish human-like recognition and associative memory. It will be most interesting to compare computer simulations of the biological and theoretical networks. Moreover, amnesia syndromes characteristic of humans with certain types of brain damage can be reproduced by discrete damage in the rat's olfactory networks. Techniques have now been developed to follow physiological events in the rat circuitries as the animals learn specific odor cues. Combining these methods with what has been learned from neurobiological experiments should lead to a far more complete picture of how, where, and when memories are stored.
In addition, the laboratory has also focused on the molecular and cellular mechanisms of aging-related neurodegeneration. Several lines of evidence indicate that changes in endosomal-lysosomal functioning contribute significantly to brain aging and Alzheimer¹s disease (AD). In accord with this, our previous work showed that experimentally induced lysosomal dysfunction triggers the development of characteristic features of the aged human brain in cultured slices of rodent brain. Included among these are i) increases in the lysosomal hydrolase cathepsin D, ii) formation of hyperphosphorylated fragments of the microtubule crosslinking protein tau, iii) depletion of synaptic proteins, iv) development of meganeurites, and v) generation of neurofibrillary tangle-like structures. The primary objective of our first project is to study how lysosomal dysfunction is involved in generating AD like pathology.
Dr. Lynch received a B.S. in Psychology from the University of Delaware and a PhD in Psychology from Princeton University prior to joining the faculty at UCI as an Assistant Professor in the Department of Psychobiology (now Neurobiology and Behavior). He is now Professor Above Scale in the Department of Psychiatry and Human Behavior with a joint appointment as Professor in Anatomy and Neurobiology.
Lauterborn, J. C., C. D. Cox, S. W. Chan, P. W. Vanderklish, G. Lynch and C. M. Gall (2020). Synaptic actin stabilization protein loss in Down syndrome and Alzheimer disease. Brain Pathol 30: 319-331.
Cox* B.M., Cox* C.D., Gunn* B.G., Le A.A., Inshishian V.C., Gall C.M., Lynch G (2019). Acquisition of temporal order requires an intact CA3 commissural/associational (C/A) feedback system in mice. Nature Comm Biol. https://doi.org/10.1038/s42003-019-0494-3. *Contributed equally.
Weisheng Wang, Brittney M. Cox, Yousheng Jia, Aliza A. Le, Conor D. Cox, Kwang M. Jung, Bowen Hou, Daniele Piomelli, Christine M. Gall* and Gary Lynch* (2018). Treating a novel plasticity defect rescues episodic memory in Fragile X model mice. Molecular Psychiatry, Nov 14. doi: 10.1038/mp.2017.221. PMID: 29133950
Wang W, Le AA, Hou B, Lauterborn JC, Cox CD, Levin ER, Lynch G, Gall CM. Memory-related synaptic plasticity is sexually dimorphic in rodent hippocampus. (2018) J Neurosci. 38:7935-51. doi: 10.1523/JNEUROSCI.0801-18.2018. PMCID: PMC6136152. (Featured in “This week in the Journal” by J. Neurosci. F1000Prime Recommended as being of special significance.)
Wang W, Jia Y, Pham D, Palmer L Jung K-W, Cox C, Rumbaugh G, Gall CM, Lynch G. (2017). Atypical Endocannabinoid Signaling Initiates a New Form of Memory-Related Plasticity at a Cortical input to Hippocampus. Cereb. Cortex, 2017 May 17:1-14. doi: 10.1093/cercor/bhx126. PMID: 28520937
Ozkan E. D., Creson T. K., Kramar E. A., Rojas C., Seese R. R., Babyan A. H., Shi Y., Lucero R., Xu X., Noebels J. L., Miller C. A., Lynch G., and Rumbaugh G. (2014). Reduced Cognition in Syngap1 Mutants Is Caused by Isolated Damage within Developing Forebrain Excitatory Neurons. Neuron. 82, 1317-1333.
Seese R. R., Chen L. Y., Cox C. D., Schulz D., Babayan A. H., Bunney W. E., Henn F. A., Gall C. M., and Lynch G. (2013). Synaptic abnormalities in the infralimbic cortex of a model of congenital depression. J. Neuroscience. 33, 13441-13448.
Lynch G., and Gall C. M. (2013). Mechanism based approaches for rescuing and enhancing cognition. Frontiers in neuroscience. 7, 143.
Babayan A. H., Kramar E. A., Barrett R. M., Jafari M., Haettig J., Chen L. Y., Rex C. S., Lauterborn J. C., Wood M. A., Gall C. M., and Lynch G. (2012). Integrin dynamics produce a delayed stage of long-term potentiation and memory consolidation. The Journal of neuroscience : the official journal of the Society for Neuroscience. 32, 12854-12861.
Kramar E. A., Babayan A. H., Gavin C. F., Cox C. D., Jafari M., Gall C. M., Rumbaugh G., and Lynch G. (2012). Synaptic evidence for the efficacy of spaced learning. Proceedings of the National Academy of Sciences of the United States of America. 109, 5121-5126.
Kramar E. A., Chen L. Y., Lauterborn J. C., Simmons D. A., Gall C. M., and Lynch G. (2012). BDNF upregulation rescues synaptic plasticity in middle-aged ovariectomized rats. Neurobiol Aging. 33, 708-719.
Baudry M., Kramar E., Xu X., Zadran H., Moreno S., Lynch G., Gall C., and Bi X. (2012). Ampakines promote spine actin polymerization, long-term potentiation, and learning in a mouse model of Angelman syndrome. Neurobiology of disease. 47, 210-215.
Rex C. S., Gavin C. F., Rubio M. D., Kramar E. A., Chen L. Y., Jia Y., Huganir R. L., Muzyczka N., Gall C. M., Miller C. A., Lynch G., and Rumbaugh G. (2010). Myosin IIb regulates actin dynamics during synaptic plasticity and memory formation. Neuron. 67, 603-617.
Chen, LY*, CS Rex*, A.H. Babayan, E.A. Kramar, G. Lynch, C.M. Galla and J.C. Lauterborn. 2010 Physiological activation of synaptic Rac > PAK signaling is defective in a mouse model of Fragile-X Syndrome. J. Neurosci. 30: 10977-10984.
Rex, C.S., L.Y. Chen, A. Sharma, J. Liu, C.M. Gall, and G. Lynch. 2009 Different Rho GTPase-dependent Signaling Pathways Initiate Sequential Steps in LTP Consolidation. J. Cell Biol. 186: 85-97. PMCID: PMC2712993
Kramár, E.A., Chen, L.Y., Brandon, N.J., Rex, C.S., Liu, F., Gall, C.M. and Lynch, G. 2009 Cytoskeletal changes underlie estradiol’s acute effects on synaptic transmission and plasticity. J. Neurosci. 29:12982-12993. PMCID: PMC2806054
Lynch G and Granger R 2008 Big Brain: The Origins and Future of Human Intelligence. Palgrave Macmillan Press, New York. (Book)
Lynch, G. C.S. Rex and C.M. Gall 2007 LTP consolidation: Substrates, explanatory power, and functional significance. Neuropharmacology, 52: 12-23. PMID: 16949110
Lynch G., Kramar E. A., Rex C. S., Jia Y., Chappas D., Gall C. M., and Simmons D. A. (2007). Brain-derived neurotrophic factor restores synaptic plasticity in a knock-in mouse model of Huntington's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience. 27, 4424-4434.
Fedulov, V., C.S. Rex, D.A. Simmons, C.M. Gall and G. Lynch. 2007 Evidence that potentiation occurs at individual synapses during learning. J. Neurosci. 27:8031-9.
Kramár, E.A., B. Lin, S. Inkindi, C.M. Gall and G. Lynch 2006 Integrin-driven actin polymerization consolidates long-term potentiation. Proc. Nat. Acad. Sci., USA, 103: 5579-5584.
Chen LY, Rex CS, Casale M, Gall CM, Lynch G (2007) Changes in synaptic morphology accompany actin signaling during LTP. J Neurosci., 27(20):5363-72.
RHD089491A (Lynch and Gall) 09/01/16-06/30/21
P50 (PI, D. Piomelli; Lynch Co-PI) 07/01/18-06/30/23
ICAL: Impact of Cannabinoids across lifespan
N00014182114 (Lynch) 12/22/17-12/21/22
Office of Naval Research
Hippocampal Networks and Episodic Memory
R01 R01MH101491 multi-PI: Wood MA, Lynch G (renewal score: top 5%)
NIMH Role of neuron-specific nucleosome remodeling in intellectual disability
Society for Neuroscience
Interdepartmental Neuroscience Program
Gillespie Neuroscience Research Facility