My laboratory is interested in two questions: the mechanisms of memory and abnormalities that underlie schizophrenia. In both cases, we seek to determine how biochemical, neuronal and network processes can work as a system to perform physiological function.
To study memory, we use slices of a region of the brain called the hippocampus, a region known to be important for memory. We have developed a means of monitoring individual synapses in the dendrites using Ca2+-sensitive dyes and optical measurement and stimulation methods. With this method, we can induce LTP at single synapses and study changes in the location and state of enzymes important in the LTP process.
Of particular interest is how memory is stored at synapses. The underlying solution is non-trivial because memories can be very long-lasting (years), while the molecules of the synapse are short-lasting. Based on the properties of an abundant multi-subunit brain protein (CaMKII) and theoretical analysis, we have developed the hypothesis that memory is stored by the complex of phosphorylated CaMKII with a synaptic membrane protein called the NMDA receptor (NMDAR). This complex forms during the induction of LTP (learning) after CaMKII becomes phosphorylated. We suspect that this complex (containing phosphorylated CaMKII) can be stable despite protein turnover and despite the presence of phosphatase that removes the phosphate. What maintains the phosphorylated state is the fact that phosphorylated subunits are active and can rephosphorylate other subunits that become dephosphorylated by phosphatase or that need to phosphorylated as a result of protein turnover (which occurs by subunit exchange).
We have tested the above hypothesis in several ways. In what is called the “erasure test”, we have induced LTP and then shown that we can erase it by applying a peptide that prevents association of CaMKII with the NMDAR. In work that have recently submitted for publication, we have done the erasure test at the behavioral level (i.e. making an animal forget by interfering with CaMKII functionAs can been seen in the EEG, the brain shows dramatic oscillations in electrical signals. We have done extensive experimental and theoretical work to understand the role of these oscillations in how information is represented in the brain. One concept we introduced is that of the theta-gamma code. Gamma oscillations are rapid (40Hz). Thus multiple gamma cycles can be nested within a single theta cycle. We believe that a unit of information (e.g. about a presented item) can be represented by the spatial pattern of cells that fire during a gamma cycle. Furthermore, the different gamma cycles within a theta cycle can represent different items. Thus, if there are 6 gamma cycles in a theta cycle (as shown), 6 items can be represented. We believe this type of information representation is fundamental to understanding the network mechanisms that store short-term and long-term memory.
A second major goal of the laboratory is to understand schizophrenia. Our approach is based on two major observations. First, EEG measurements on subjects with schizophrenia show that delta frequency (1-4 Hz) oscillations are elevated in the disease in the awake state. Second, normal subjects, when given drugs that block (antagonize) NMDARs, acutely develop positive and negative symptoms of schizophrenia. A major contribution of our laboratory has been to show that NMDA antagonist can generate delta oscillations in the thalamus and that these abnormal oscillations can interfere with functions known to show deficits in schizophrenia. We hope that by understanding how these abnormal delta oscillations are generated, new treatment strategies can be developed. One reason for particular optimism is that recent genetic studies have identified risk genes for schizophrenia, many of which are central to thalamic processes that we have been studying.
Lisman, J. (2017). "Glutamatergic synapses are structurally and biochemically complex because of multiple plasticity processes: long-term potentiation, long-term depression, short-term potentiation and scaling." Philos Trans R Soc Lond B Biol Sci 372(1715).
Liu, K. K., M. F. Hagan and J. E. Lisman (2017). "Gradation (approx. 10 size states) of synaptic strength by quantal addition of structural modules." Philos Trans R Soc Lond B Biol Sci 372(1715).
Richard, E. A., E. Khlestova, R. Nanu and J. E. Lisman (2017). "Potential synergistic action of 19 schizophrenia risk genes in the thalamus." Schizophr Res 180: 64-69.
Anticevic, A. and J. Lisman (2017). "How Can Global Alteration of Excitation/Inhibition Balance Lead to the Local Dysfunctions That Underlie Schizophrenia?" Biol Psychiatry.
Keck, T., T. Toyoizumi, L. Chen, B. Doiron, D. E. Feldman, K. Fox, W. Gerstner, P. G. Haydon, M. Hubener, H. K. Lee, J. E. Lisman, T. Rose, F. Sengpiel, D. Stellwagen, M. P. Stryker, G. G. Turrigiano and M. C. van Rossum (2017). "Integrating Hebbian and homeostatic plasticity: the current state of the field and future research directions." Philos Trans R Soc Lond B Biol Sci 372(1715).
Brandalise, F., S. Carta, F. Helmchen, J. Lisman and U. Gerber (2016). "Dendritic NMDA spikes are necessary for timing-dependent associative LTP in CA3 pyramidal cells." Nat Commun 7: 13480.
Khlestova, E., J. W. Johnson, J. H. Krystal and J. Lisman (2016). "The Role of GluN2C-Containing NMDA Receptors in Ketamine's Psychotogenic Action and in Schizophrenia Models." J Neurosci 36(44): 11151-11157.
Lisman J. 2016."Low-Frequency Brain Oscillations in Schizophrenia." JAMA Psychiatry 73: 298-9.
Duan AR, Varela C, Zhang Y, Shen Y, Xiong L, Wilson MA, Lisman J. 2015. "Delta frequency optogenetic stimulation of the thalamic nucleus reuniens is sufficient to produce working memory deficits: relevance to schizophrenia." Biol Psychiatry 77: 1098-107.
Lisman J. 2015. "The challenge of understanding the brain: where we stand in 2015." Neuron 86: 864-82.
Lisman JE, Jensen O. 2013. "The theta-gamma neural code." Neuron 77:1002-16.
Lisman J, Yasuda R, Raghavachari S. 2012. "Mechanisms of CaMKII action in long-term potentiation." Nat Rev Neurosci 13:169-82.
Last edit: April 7, 2017