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

Abstract

The input-output relationships in neural circuits are determined not only by synaptic efficacy but also by neuronal excitability. Activitydependent 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 (V th ) 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 V th 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 StatementLong-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.

Activation of PLCβ1 enhances endocannabinoid mobilization to restore hippocampal spike-timing-dependent potentiation and contextual fear memory impaired by Alzheimer’s amyloidosis

“…3 f). These results indicate that mGluR5-mediated LTD is robust to AβO [ 102 ] and is independent of mGluR5-mediated PLCβ-dependent eCB mobilization, which is consistent with previous studies [ 103 , 104 ]. Therefore, it is crucial to target more specific downstream pathways of mGluR5 to fully understand the effect of AβO on mGluR5.…”

Lights on Endocannabinoid-Mediated Synaptic Potentiation

“…This LTD of inhibitory transmission (i-LTD) then facilitates the release of glutamate at CA3–CA1 synapses promoting a local LTP. This eCB-mediated metaplasticity can be induced with various cell conditioning paradigms, and most notably subthreshold stimulations (HFS, LFS, TBS or ITDP; Chevaleyre and Castillo, 2003 , 2004 ; Zhu and Lovinger, 2007 ; Lin et al, 2011 ; Pan et al, 2011 ; Xu et al, 2012 ; Basu et al, 2013 ; Orr et al, 2014 ; Monory et al, 2015 ; Silva-Cruz et al, 2017 ; Kim et al, 2019 ). (D) Heterosynaptic eCB-LTP involving astrocytes at CA3–CA1 synapses.…”

“…long-lasting neural changes induced by activity at a given time, and that modulate subsequently induced plasticity (Abraham, 2008 ), orchestrated by eCBs. This i-LTD is finely tuned by the parallel activation of CB 1 R on GABAergic or glutamatergic cells (Monory et al, 2015 ) and is also accompanied by changes in excitability enhancing the spiking probability in response to a given EPSP, i.e ., EPSP-to-spike potentiation (Chevaleyre and Castillo, 2003 ; Orr et al, 2014 ; Kim et al, 2019 ), and by structural changes (Monory et al, 2015 ; Hu et al, 2019 ) both eCB-mediated. Interestingly, a circuit-based synaptic learning rule, consisting of paired stimulation of the perforant path and Schaffer collaterals, induced an input-timing-dependent heterosynaptic LTP at CA3-CA1 but not at cortical-CA1 synapses (Xu et al, 2012 ; Basu et al, 2013 ).…”

Effects of Different Degrees of Carotid Artery Stenosis on the Expression of XIAP and Smac in the Ischemic Penumbra of Rats with Cerebral Ischemia-Reperfusion

“…9 It has been shown that more than 50% of rats have neuronal necrosis in the hippocampal CA1 region one month after the establishment of rat models of SES. 10 There is no doubt that CAS can lead to CI, but the mechanism of brain injury caused by CAS is not clear.…”