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Inhibitory autophosphorylation of CaMKII controls PSD association, plasticity, and learning
Ype Elgersma1, Nikolai B Fedorov, Sami Ikonen
1Department of Neurobiology, Department of Psychiatry, Department of Psychology, Brain Research Institute, University of California, Los Angeles, CA 90095, USA.
Abstract:
To investigate the function of the alpha calcium-calmodulin-dependent kinase II (alphaCaMKII) inhibitory autophosphorylation at threonines 305 and/or 306, we generated knockin mice that express alphaCaMKII that cannot undergo inhibitory phosphorylation. In addition, we generated mice that express the inhibited form of alphaCaMKII, which resembles the persistently phosphorylated kinase at these sites. Our data demonstrate that blocking inhibitory phosphorylation increases CaMKII in the postsynaptic density (PSD), lowers the threshold for hippocampal long-term potentiation (LTP), and results in hippocampal-dependent learning that seems more rigid and less fine-tuned. Mimicking inhibitory phosphorylation dramatically decreased the association of CaMKII with the PSD and blocked both LTP and learning. These data demonstrate that inhibitory phosphorylation has a critical role in plasticity and learning.
Insights
Blocking inhibitory phosphorylation of alpha calcium-calmodulin-dependent kinase II (alphaCaMKII) enhances synaptic plasticity and learning. Conversely, mimicking this phosphorylation impairs these functions, highlighting its critical role.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Alpha calcium-calmodulin-dependent kinase II (alphaCaMKII) is crucial for synaptic plasticity and learning.
- Autophosphorylation at threonine 305/306 regulates alphaCaMKII activity.
- The precise role of this inhibitory phosphorylation in vivo remains unclear.
Purpose of the Study:
- To elucidate the function of alphaCaMKII inhibitory autophosphorylation at threonines 305 and/or 306.
- To investigate the impact of altered alphaCaMKII phosphorylation states on synaptic plasticity and learning.
Main Methods:
- Generation of knockin mice expressing non-phosphorylatable alphaCaMKII.
- Generation of knockin mice expressing persistently phosphorylated alphaCaMKII.
- Assessment of CaMKII localization in the postsynaptic density (PSD).
- Electrophysiological recordings of hippocampal long-term potentiation (LTP).
- Evaluation of hippocampal-dependent learning behaviors.
Main Results:
- Blocking inhibitory phosphorylation increased PSD-localized alphaCaMKII, lowered the LTP threshold, and led to rigid learning.
- Mimicking inhibitory phosphorylation reduced PSD association, blocked LTP, and impaired learning.
- Altered alphaCaMKII phosphorylation states significantly impact synaptic plasticity and cognitive function.
Conclusions:
- Inhibitory autophosphorylation of alphaCaMKII at T305/306 is critical for regulating synaptic plasticity and learning.
- This phosphorylation controls alphaCaMKII's interaction with the PSD, influencing its function.
- Targeting alphaCaMKII phosphorylation may offer therapeutic avenues for cognitive disorders.