CaMKII nitrosylation in the age-related decline of synaptic plasticity

Cognitive decline majorly affects quality of life in the general aging population; this is further exacerbated by an
increased risk for neurodegenerative diseases. The general age-related cognitive decline is thought to be
mainly due to impaired synaptic function, not loss of neurons. Similarly, while neurodegenerative diseases do
involve loss of neurons, there is also significantly impaired synaptic function in the surviving neurons, For
instance, amyloid β oligomers (Aβ) are major pathological agents in as Alzheimer's disease (AD) and cause
acute impairments in long-term potentiation (LTP) of excitatory synapses in the hippocampus, even at time
points and concentrations insufficient to induce any significant neuronal cell death. Here we will test our
hypotheses that the LTP impairments related to normal aging versus AD (i) both involve mis-regulation of the
Ca2+/calmodulin(CaM)-dependent protein kinase II (CaMKII), but (ii) by fundamentally different mechanisms to
(iii) result in the distinct forms of LTP impairment in normal aging versus AD. Specifically, we hypothesize that
CaMKII hypo-nitrosylation directly causes the impairments in aging, but not the Aβ-induced impairments
(which may instead even involve hyper-nitrosylation). Additionally, we hypothesize that hypo-nitrosylation
reduces LTP by chronic long-term effects on synapse composition (including CaMKII itself), while the Aβ effects
instead involve acute mis-regulation of CaMKII.
LTP is well-known to require CaMKII and its Ca2+-independent “autonomous” activity that is generated by
autophosphorylation of T286. Additionally, two alternative ways to generate autonomous activity have been
described by my lab: Binding to the NMDA-receptor subunit GluN2B and S-nitrosylation of C280+C289. Indeed,
CaMKII binding to GluN2B is also required for normal LTP and for the CaMKII movement to excitatory synapses
during LTP. The functions of CaMKII nitrosylation in LTP and other forms of synaptic plasticity will be elucidated
here. Intriguingly, previous studies have shown that aging is accompanied by hypo-nitrosylation of neuronal
proteins, including CaMKII, in both mice and humans. Additionally, preliminary studies indicated that
nitrosylation causes CaMKII movement to excitatory synapses, and that this requires regulated CaMKII binding
to GluN2B. i.e. the same mechanism that is required for the LTP-induced CaMKII movement.
In three related but independent aims, our proposal will determine the specific involvement of CaMKII
nitrosylation in the LTP impairments related to normal aging versus AD (with the expectation for fundamentally
distinct CaMKII mis-regulation). First, we will determine the regulatory mechanisms for synaptic CaMKII
localization by nitrosylation. Then, we will determine the functions of CaMKII nitrosylation in the distinct
impairment of LTP related to normal aging versus AD. Finally, we will determine the effects of CaMKII
nitrosylation on learning and memory function in behavioral tasks.

Grant Number: 5R01AG067713-05
NIH Institute/Center: NIH
Principal Investigator: K. Ulrich Bayer