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Mentor: Johannes W. Hell, PhD
Year Entered Into Program: 2003 (MSTP) 2005 (PhD Program)
PhD Institution: University of Iowa, 2010 (MD, PhD)
Chemical synapses are highly dynamic structures that are capable of undergoing structural and physiological changes in response to the pattern and intensity of their stimulation. These activity-dependent changes, termed synaptic plasticity, have long been recognized as a physiological substrate for learning and memory. Long-term potentiation (LTP) is the most commonly studied form of synaptic plasticity. Induction of LTP is critically dependent on the activation of N-methyl-D-aspartate-type glutamate receptors (NMDA-R) and Ca2+/Calmodulin-Dependent Kinase II (CaMKII). Postsynaptic calcium influx through NMDA-R triggers the activation of CaMKII, which translocates to the postsynaptic signaling sites through its interactions with the NMDA-R subunits NR1 and NR2B. The significance of CaMKII’s translocation is not fully known, however we hypothesize that it is an early molecular event that is necessary for the expression of synaptic plasticity. Our laboratory has developed two strains of mice with targeted mutations to NR1 and NR2B that are unable to bind to CaMKII. These two strains of mice will be used to test the significance of CaMKII translocation to the postsynaptic density. Biochemical analysis of forebrain homogenates in NR2B knock-in mice demonstrates a dramatic reduction in the association of NR2B and CaMKII compared to WT littermates. Our preliminary electrophysiological studies suggest that basal synaptic transmission is not altered in NR2B KI mice, which demonstrate similar input-output relationships and paired-pulse facilitation. However, NR2B KI mice are deficient in their ability to exhibit LTP, demonstrating only 122 ± 4% potentiation compared to WT litter-matched controls with 157 ± 7% potentiation. These results suggest that NR2B-mediated targeting of CaMKII to the postsynaptic density plays a critical role in LTP.
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