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Metaplastic reinforcement of long-term potentiation in rat hippocampal area CA2 by cholinergic receptor activation

View ORCID ProfileAmrita Benoy, Mohammad Zaki Bin Ibrahim, View ORCID ProfileThomas Behnisch, View ORCID ProfileSreedharan Sajikumar
doi: https://doi.org/10.1101/2020.10.27.358275
Amrita Benoy
1Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117 597
2Life Sciences Institute Neurobiology Programme, National University of Singapore, Singapore 117 456
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Mohammad Zaki Bin Ibrahim
1Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117 597
2Life Sciences Institute Neurobiology Programme, National University of Singapore, Singapore 117 456
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Thomas Behnisch
3Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
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Sreedharan Sajikumar
1Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117 597
2Life Sciences Institute Neurobiology Programme, National University of Singapore, Singapore 117 456
4Healthy Longevity Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117 456
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  • For correspondence: phssks@nus.edu.sg
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Abstract

Hippocampal CA2, an inconspicuously positioned area between the well-studied CA1 and CA3 subfields, has captured research interest in recent years due to its role in the formation of social memory. The effects of synaptic depression for subsequent long-term potentiation (LTP) of synaptic transmission at entorhinal cortical (EC)-CA2 and Schaffer collateral (SC)-CA2 synapses have not been previously explored. Here we show that cholinergic receptor activation with the non-selective cholinergic agonist carbachol (CCh) triggers a long-term synaptic depression (CCh-LTD) of field excitatory postsynaptic potentials at EC- and SC-CA2 synapses in the hippocampus of adult rats. The activation of muscarinic acetylcholine receptors (mAChRs) is critical for the induction of an early phase (<100 min) of CCh-LTD, with a strong dependency upon M3 mAChR activation and a weaker one by M1 mAChRs. Interestingly, muscarinic M2 and nicotinic receptor activation are crucially involved in the late phase (>100 min) of CCh-LTD. Importantly, CCh priming lowers the threshold, in a protein synthesis-dependent manner, for the late maintenance of LTP that can be subsequently induced by high-frequency electrical stimulation at EC- or SC-CA2 pathways. The results demonstrate that CA2 synaptic learning rules are modified in a metaplastic manner, wherein synaptic modifications triggered by cholinergic stimulation can dictate the outcome of future plasticity events. Moreover, the observed enabling of late LTP at EC inputs to CA2 following the priming stimulus co-exists with concurrent sustained CCh-LTD at SC-CA2 and is dynamically scaled by modulation of SC-CA2 synaptic transmission.

Significance Statement The release of the neuromodulator acetylcholine is critically involved in processes of hippocampus-dependent memory formation. Cholinergic afferents originating in the medial septum and diagonal bands of Broca terminating in the hippocampal area CA2 might play an important role in the modulation of area-specific synaptic plasticity. Our findings demonstrate that cholinergic receptor activation induces a long-term depression of synaptic transmission at entorhinal cortical- and Schaffer collateral-CA2 synapses. This cholinergic activation-mediated long-term depression displays a bidirectional metaplastic switch to long-term potentiation on a future timescale. This suggests that such bidirectional synaptic modifications triggered by the dynamic modulation of tonic cholinergic receptor activation may support the formation of CA2-dependent memories given the increased hippocampal cholinergic tone during active wakefulness observed in exploratory behaviour.

Competing Interest Statement

The authors have declared no competing interest.

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Posted October 28, 2020.
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Metaplastic reinforcement of long-term potentiation in rat hippocampal area CA2 by cholinergic receptor activation
Amrita Benoy, Mohammad Zaki Bin Ibrahim, Thomas Behnisch, Sreedharan Sajikumar
bioRxiv 2020.10.27.358275; doi: https://doi.org/10.1101/2020.10.27.358275
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Metaplastic reinforcement of long-term potentiation in rat hippocampal area CA2 by cholinergic receptor activation
Amrita Benoy, Mohammad Zaki Bin Ibrahim, Thomas Behnisch, Sreedharan Sajikumar
bioRxiv 2020.10.27.358275; doi: https://doi.org/10.1101/2020.10.27.358275

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