Leslie Griffith, M.D., PhD

Nancy Lurie Marks Professor of Neuroscience
Department of Biology
Brandeis University
(October 12, 2017)

Local Translation of CaMKII Regulates Plasticity of Spontaneous Release

It has been known for many years that long-term memory requires the synthesis of new protein molecules at synapses. What these proteins are and how their function is specifically regulated by stimuli that drive formation of memory is still an open question.

CaMKII is required for memory formation in both rodents and the fruit fly Drosophila. To better understand the regulation of CaMKII synthesis, the Griffith lab generated null mutations in the CaMKII gene. These animals survived until pupation due to maternally deposited CaMKII mRNA and protein. Interestingly, the maternal CaMKII was not able to localize to synapses, suggesting that synaptic CaMKII, the pool most likely to be involved in plasticity and memory formation, required zygotically synthesized mRNA. A possible mechanism suggested itself when it was shown that the maternal mRNA lacked the long 3’UTR of the zygotic mRNA. This region of mRNAs is associated with translational regulation by microRNAs.

To test the role of local translation of the CaMKII mRNA, the Griffith lab utilized a plasticity paradigm that required local protein synthesis. Spaced depolarization of the larval neuromuscular junction (NMJ) has a profound effect on the frequency of miniature end plate potentials (minis), which increase by 4-5X. They found that CaMKII mutant larva completely lacked this plasticity. Rescue of the mutant with a transgene that encoded a version of the CaMKII gene that lacked the long 3’UTR failed to rescue plasticity, whereas a transgene with the entire gene completely restored the increase in minis. Adults with these rescue constructs were tested for long-term memory in an odor-sugar appetitive associative memory assay. Only animals in which the transgene contained the long 3’UTR were able to form memory.
To test the role of microRNAs in plasticity, the Griffith lab overexpressed mir-289, a microRNA shown previously to regulate CaMKII at the larval NMJ. mir-289 also blocked mini plasticity when expressed in either the presynaptic or postsynaptic cell. In aggregate, these results suggest that local translation of CaMKII is critical to both synaptic plasticity and to memory formation.