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Association of mGluR-Dependent LTD of Excitatory Synapses with Endocannabinoid-Dependent LTD of Inhibitory Synapses Leads to EPSP to Spike Potentiation in CA1 Pyramidal Neurons.
J Neurosci. 2019 01 09; 39(2):224-237.JN

Abstract

The input-output relationships in neural circuits are determined not only by synaptic efficacy but also by neuronal excitability. Activity-dependent alterations of synaptic efficacy have been extensively investigated, but relatively less is known about how the neuronal output is modulated when synaptic efficacy changes are associated with neuronal excitability changes. In this study, we demonstrate that paired pulses of low-frequency stimulation (PP-LFS) induced metabotropic glutamate receptor (mGluR)-dependent LTD at Schaffer collateral (SC)-CA1 synapses in Sprague Dawley rats (both sexes), and this LTD was associated with EPSP to spike (E-S) potentiation, leading to the increase in action potential (AP) outputs. Threshold voltage (Vth) for APs evoked by synaptic stimulation and that by somatic current injection were hyperpolarized significantly after PP-LFS. Blockers of GABA receptors mimicked and occluded PP-LFS effects on E-S potentiation and Vth hyperpolarization, suggesting that suppression of GABAergic mechanisms is involved in E-S potentiation after PP-LFS. Indeed, IPSCs and tonic inhibitory currents were reduced after PP-LFS. The IPSC reduction was accompanied by increased paired-pulse ratio, and abolished by AM251, a blocker for Type 1 cannabinoid receptors, suggesting that PP-LFS suppresses presynaptic GABA release by mGluR-dependent endocannabinoids signaling. By contrast, a Group 1 mGluR agonist, 3, 5-dihydroxyphenylglycine, induced LTD at SC-CA1 synapses but failed to induce significant IPSC reduction and AP output increase. We propose that mGluR signaling that induces LTD coexpression at excitatory and inhibitory synapses regulates an excitation-inhibition balance to increase neuronal output in CA1 neurons.SIGNIFICANCE STATEMENT Long-lasting forms of synaptic plasticity are usually associated with excitability changes, the ability to fire action potentials. However, excitability changes have been regarded to play subsidiary roles to synaptic plasticity in modifying neuronal output. We demonstrate that, when metabotropic glutamate receptor-dependent LTD is induced by paired pulses of low-frequency stimulation, the action potential output in response to a given input paradoxically increases, indicating that increased excitability is more powerful than synaptic depression. This increase is mediated by the suppression of a presynaptic GABA release via metabotropic glutamate receptor-dependent endocannabinoid signaling. Our study shows that neuronal output changes do not always follow the direction of synaptic plasticity at excitatory synapses, highlighting the importance of regulating inhibitory tone via endocannabinoid signaling.

Authors+Show Affiliations

Department of Physiology. Biomembrane Plasticity Research Center, and. Neuroscience Research Center, Seoul National University College of Medicine, Seoul 110-799, Korea, and.Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34047, Korea.Department of Physiology. Biomembrane Plasticity Research Center, and. Neuroscience Research Center, Seoul National University College of Medicine, Seoul 110-799, Korea, and.Department of Physiology, wonkyung@snu.ac.kr. Biomembrane Plasticity Research Center, and. Neuroscience Research Center, Seoul National University College of Medicine, Seoul 110-799, Korea, and.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30459224

Citation

Kim, Hye-Hyun, et al. "Association of mGluR-Dependent LTD of Excitatory Synapses With Endocannabinoid-Dependent LTD of Inhibitory Synapses Leads to EPSP to Spike Potentiation in CA1 Pyramidal Neurons." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 39, no. 2, 2019, pp. 224-237.
Kim HH, Park JM, Lee SH, et al. Association of mGluR-Dependent LTD of Excitatory Synapses with Endocannabinoid-Dependent LTD of Inhibitory Synapses Leads to EPSP to Spike Potentiation in CA1 Pyramidal Neurons. J Neurosci. 2019;39(2):224-237.
Kim, H. H., Park, J. M., Lee, S. H., & Ho, W. K. (2019). Association of mGluR-Dependent LTD of Excitatory Synapses with Endocannabinoid-Dependent LTD of Inhibitory Synapses Leads to EPSP to Spike Potentiation in CA1 Pyramidal Neurons. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 39(2), 224-237. https://doi.org/10.1523/JNEUROSCI.2935-17.2018
Kim HH, et al. Association of mGluR-Dependent LTD of Excitatory Synapses With Endocannabinoid-Dependent LTD of Inhibitory Synapses Leads to EPSP to Spike Potentiation in CA1 Pyramidal Neurons. J Neurosci. 2019 01 9;39(2):224-237. PubMed PMID: 30459224.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Association of mGluR-Dependent LTD of Excitatory Synapses with Endocannabinoid-Dependent LTD of Inhibitory Synapses Leads to EPSP to Spike Potentiation in CA1 Pyramidal Neurons. AU - Kim,Hye-Hyun, AU - Park,Joo Min, AU - Lee,Suk-Ho, AU - Ho,Won-Kyung, Y1 - 2018/11/20/ PY - 2017/10/11/received PY - 2018/10/16/revised PY - 2018/11/08/accepted PY - 2018/11/22/pubmed PY - 2019/10/17/medline PY - 2018/11/22/entrez KW - E-I balance KW - E-S potentiation KW - endocannabinoid KW - i-LTD KW - mGluR-LTD SP - 224 EP - 237 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 39 IS - 2 N2 - The input-output relationships in neural circuits are determined not only by synaptic efficacy but also by neuronal excitability. Activity-dependent alterations of synaptic efficacy have been extensively investigated, but relatively less is known about how the neuronal output is modulated when synaptic efficacy changes are associated with neuronal excitability changes. In this study, we demonstrate that paired pulses of low-frequency stimulation (PP-LFS) induced metabotropic glutamate receptor (mGluR)-dependent LTD at Schaffer collateral (SC)-CA1 synapses in Sprague Dawley rats (both sexes), and this LTD was associated with EPSP to spike (E-S) potentiation, leading to the increase in action potential (AP) outputs. Threshold voltage (Vth) for APs evoked by synaptic stimulation and that by somatic current injection were hyperpolarized significantly after PP-LFS. Blockers of GABA receptors mimicked and occluded PP-LFS effects on E-S potentiation and Vth hyperpolarization, suggesting that suppression of GABAergic mechanisms is involved in E-S potentiation after PP-LFS. Indeed, IPSCs and tonic inhibitory currents were reduced after PP-LFS. The IPSC reduction was accompanied by increased paired-pulse ratio, and abolished by AM251, a blocker for Type 1 cannabinoid receptors, suggesting that PP-LFS suppresses presynaptic GABA release by mGluR-dependent endocannabinoids signaling. By contrast, a Group 1 mGluR agonist, 3, 5-dihydroxyphenylglycine, induced LTD at SC-CA1 synapses but failed to induce significant IPSC reduction and AP output increase. We propose that mGluR signaling that induces LTD coexpression at excitatory and inhibitory synapses regulates an excitation-inhibition balance to increase neuronal output in CA1 neurons.SIGNIFICANCE STATEMENT Long-lasting forms of synaptic plasticity are usually associated with excitability changes, the ability to fire action potentials. However, excitability changes have been regarded to play subsidiary roles to synaptic plasticity in modifying neuronal output. We demonstrate that, when metabotropic glutamate receptor-dependent LTD is induced by paired pulses of low-frequency stimulation, the action potential output in response to a given input paradoxically increases, indicating that increased excitability is more powerful than synaptic depression. This increase is mediated by the suppression of a presynaptic GABA release via metabotropic glutamate receptor-dependent endocannabinoid signaling. Our study shows that neuronal output changes do not always follow the direction of synaptic plasticity at excitatory synapses, highlighting the importance of regulating inhibitory tone via endocannabinoid signaling. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/30459224/Association_of_mGluR_Dependent_LTD_of_Excitatory_Synapses_with_Endocannabinoid_Dependent_LTD_of_Inhibitory_Synapses_Leads_to_EPSP_to_Spike_Potentiation_in_CA1_Pyramidal_Neurons_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=30459224 DB - PRIME DP - Unbound Medicine ER -