Multiple data support a critical role of the interaction of CaMKII and the NMDA receptor subunit, NR2B, in LTP induction. Several recent studies, including those from our lab, also suggested a role of this binding in LTP maintenance. We are currently developing a methodology to monitor CaMKII-NR2B binding in single spines using FLIM/FRET technique. For doing this we will tag endogenous NR2B and CaMKII with fluorescent proteins using CRISPR-Cas9 method. LTP is induced by glutamate uncaging on single spines.
If stable post-translational molecular modifications maintain LTP and memories for months and years, how is memory protected against molecular turnover, which can be as fast as a few days? John Lisman’s original proposal was that an individual member of a group of similar kinase molecules can be replaceable while the group as a whole can still maintain its active state. Recently a similar mechanism has received experimental support in in vitro studies. In this project we aim to obtain experimental evidence for this mechanism in living cells.
Compelling evidence has emerged that LTP and memories are stored, at least in part, by structural modifications of synapses. In this project we cooperate with a group of physicists to explore how variable-size post-synaptic macro-molecular complexes can be stably maintained over time. A specific role of CaMKII in this process is also addressed.
We are investigating the possibility of treating memory deficits in Alzheimer’s disease by controlling hippocampal monoamines in mouse model, Tg2576.
In projects # 5 and #6 we investigate avolition (a negative symptom in schizophrenia), impaired working memory and severe impulsivity. Using genetically engineered mice as a model system and diverse contemporary neuroscience told such as quantitative behavior, computational phenotyping, viral neuronal tracing, in vivo optrode recording, and optogenetic/chemogenetic manipulation, we not only try to dissect neural mechanisms, but also investigate potential therapeutic directions.