Abstract
Calcium entry and the subsequent activation of CaMKII trigger synaptic plasticity in many brain regions. The induction of long-term potentiation (LTP) in the CA1 region of the hippocampus requires a relatively high amount of calcium-calmodulin. This requirement is usually explained, based on in vitro and theoretical studies, by the low affinity of CaMKII for calmodulin. An untested hypothesis, however, is that calmodulin is not randomly distributed within the spine and its targeting within the spine regulates LTP. We have previously shown that overexpression of neurogranin enhances synaptic strength in a calmodulin-dependent manner. Here, using post-embedding immunogold labeling, we show that calmodulin is not randomly distributed, but spatially organized in the spine. Moreover, neurogranin regulates calmodulin distribution such that its overexpression concentrates calmodulin closer to the plasma membrane, where a high level of CaMKII immunogold labeling is also found. Interestingly, the targeting of calmodulin by neurogranin results in lowering the threshold for LTP induction. These findings highlight the significance of calmodulin targeting within the spine in synaptic plasticity.
Highlights
In CA1 region of the hippocampus, long-lasting changes in synaptic efficacy depend on neuronal activity and are widely accepted as the cellular correlates of learning and memory formation [1,2,3]
The theory that a high CaM concentration is required for CaM-dependent protein kinase II (CaMKII) activation because of its low affinity for CaM cannot fully explain the lack of sufficient CaMKII activation to produce long-term potentiation (LTP)-like changes when CaM is overexpressed
The requirement of a relatively high level of Ca2+ for LTP induction is usually explained by the low affinity of CaM to CaMKII, whose activation is required for LTP expression
Summary
In CA1 region of the hippocampus, long-lasting changes in synaptic efficacy depend on neuronal activity and are widely accepted as the cellular correlates of learning and memory formation [1,2,3]. LTP induction requires the activation of NMDA receptors and a relatively large increase (a few micromolars) in Ca2+ concentration within dendritic spines. This increase in local Ca2+ over a short period of time (a few seconds) causes a conformational change in calmodulin (CaM) allowing it to activate Ca2+/CaM-dependent protein kinase II (CaMKII), which mediates AMPA receptor (AMPAR) delivery to synapses. A small increase in postsynaptic Ca2+ causes CaM to activate calcineurin, resulting in the expression of long-term depression (LTD). Through its activation of two different prominent pathways within the same spine, CaM can lead to either LTP or LTD
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