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 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 long-term depression (LTD) at Schaffer collateral (SC)-CA1 synapses in Sprague-Dawley rats (both sexes), and this LTD was associated with excitatory postsynaptic potential 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, inhibitory postsynaptic currents (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 co-expression 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 (AP). However, excitability changes have been regarded to play subsidiary roles to synaptic plasticity in modifying neuronal output. We demonstrate that when metabotropic glutamate receptor (mGluR)-dependent long term depression is induced by paired pulses of low-frequency stimulation, the AP 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 mGluR-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.