Heparan Sulfates Regulate Axonal Excitability and Context Generalization through Ca2+/Calmodulin-Dependent Protein Kinase II

Our previous studies demonstrated that enzymatic removal of highly sulfated heparan sulfates with heparinase 1 impaired axonal excitability and reduced expression of ankyrin G at the axon initial segments in the CA1 region of the hippocampus ex vivo, impaired context discrimination in vivo, and incr...

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Published in:Cells (Basel, Switzerland) Switzerland), 2023-02, Vol.12 (5), p.744
Main Authors: Song, Inseon, Kuznetsova, Tatiana, Baidoe-Ansah, David, Mirzapourdelavar, Hadi, Senkov, Oleg, Hayani, Hussam, Mironov, Andrey, Kaushik, Rahul, Druzin, Michael, Johansson, Staffan, Dityatev, Alexander
Format: Article
Language:English
Subjects:
Ablation
Action potential
ankyrin G
Ankyrins
axon initial segment
axonal excitability
Ca2+/calmodulin-dependent protein kinase II
Calcium-binding protein
Calmodulin
Chondroitin sulfate
context discrimination
Excitability
extracellular matrix
Fear conditioning
Heparan sulfate
Heparan sulfate proteoglycans
Hippocampus
Hypotheses
Inhibitory postsynaptic potentials
Injection
Kinases
Phosphatase
Phosphorylation
Proteins
Sulfates
synaptic plasticity
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Summary:Our previous studies demonstrated that enzymatic removal of highly sulfated heparan sulfates with heparinase 1 impaired axonal excitability and reduced expression of ankyrin G at the axon initial segments in the CA1 region of the hippocampus ex vivo, impaired context discrimination in vivo, and increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity in vitro. Here, we show that in vivo delivery of heparinase 1 in the CA1 region of the hippocampus elevated autophosphorylation of CaMKII 24 h after injection in mice. Patch clamp recording in CA1 neurons revealed no significant heparinase effects on the amplitude or frequency of miniature excitatory and inhibitory postsynaptic currents, while the threshold for action potential generation was increased and fewer spikes were generated in response to current injection. Delivery of heparinase on the next day after contextual fear conditioning induced context overgeneralization 24 h after injection. Co-administration of heparinase with the CaMKII inhibitor (autocamtide-2-related inhibitory peptide) rescued neuronal excitability and expression of ankyrin G at the axon initial segment. It also restored context discrimination, suggesting the key role of CaMKII in neuronal signaling downstream of heparan sulfate proteoglycans and highlighting a link between impaired CA1 pyramidal cell excitability and context generalization during recall of contextual memories.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells12050744