Abstract

BackgroundHippocampal CA1 pyramidal neurons receive two excitatory glutamatergic synaptic inputs: their most distal dendritic regions in the stratum lacunosum-moleculare (SLM) are innervated by the perforant path (PP), originating from layer III of the entorhinal cortex, while their more proximal regions of the apical dendrites in the stratum radiatum (SR) are innervated by the Schaffer-collaterals (SC), originating from hippocampal CA3 neurons. Endocannabinoids (eCBs) are naturally occurring mediators capable of modulating both GABAergic and glutamatergic synaptic transmission and plasticity via the CB1 receptor. Previous work on eCB modulation of excitatory synapses in the CA1 region largely focuses on the SC pathway. However, little information is available on whether and how eCBs modulate glutamatergic synaptic transmission and plasticity at PP synapses.Methodology/Principal FindingsBy employing somatic and dendritic patch-clamp recordings, Ca2+ uncaging, and immunostaining, we demonstrate that there are significant differences in low-frequency stimulation (LFS)- or DHPG-, an agonist of group I metabotropic glutamate receptors (mGluRs), induced long-term depression (LTD) of excitatory synaptic transmission between SC and PP synapses in the same pyramidal neurons. These differences are eliminated by pharmacological inhibition with selective CB1 receptor antagonists or genetic deletion of the CB1 receptor, indicating that these differences likely result from differential modulation via a CB1 receptor-dependent mechanism. We also revealed that depolarization-induced suppression of excitation (DSE), a form of short-term synaptic plasticity, and photolysis of caged Ca2+-induced suppression of Excitatory postsynaptic currents (EPSCs) were less at the PP than that at the SC. In addition, application of WIN55212 (WIN) induced a more pronounced inhibition of EPSCs at the SC when compared to that at the PP.Conclusions/SignificanceOur results suggest that CB1 dependent LTD and DSE are differentially expressed at the PP versus SC synapses in the same neurons, which may have an impact on synaptic scaling, integration and plasticity of hippocampal CA1 pyramidal neurons.

Highlights

  • Hippocampal CA1 pyramidal neurons receive two anatomically segregated glutamatergic synaptic inputs: their most distal dendritic regions in the stratum lacunosum-moleculare (SLM) receive direct sensory input from layer III neurons of the entorhinal cortex through the perforant path (PP) pathway, while their more proximal regions of the apical dendrites in the stratum radiatum (SR) receive information from hippocampal CA3 neurons through the Schaffer-collateral (SC) pathway

  • Conclusions/Significance: Our results suggest that CB1 dependent long-term depression (LTD) and depolarization-induced suppression of excitation (DSE) are differentially expressed at the PP versus SC synapses in the same neurons, which may have an impact on synaptic scaling, integration and plasticity of hippocampal CA1 pyramidal neurons

  • To determine whether eCBs are involved in DHPG-induced LTD of excitatory glutamatergic synaptic transmission at the PP and SC of rat hippocampal CA1 pyramidal neurons, we employed the whole-cell patch clamp recordings of Excitatory postsynaptic currents (EPSCs) in response to independent stimuli of the PP and SC of the same pyramidal neurons in the presence of DHPG

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Summary

Introduction

Hippocampal CA1 pyramidal neurons receive two anatomically segregated glutamatergic synaptic inputs: their most distal dendritic regions in the stratum lacunosum-moleculare (SLM) receive direct sensory input from layer III neurons of the entorhinal cortex through the perforant path (PP) pathway, while their more proximal regions of the apical dendrites in the stratum radiatum (SR) receive information from hippocampal CA3 neurons through the Schaffer-collateral (SC) pathway. Hippocampal CA1 pyramidal neurons receive two excitatory glutamatergic synaptic inputs: their most distal dendritic regions in the stratum lacunosum-moleculare (SLM) are innervated by the perforant path (PP), originating from layer III of the entorhinal cortex, while their more proximal regions of the apical dendrites in the stratum radiatum (SR) are innervated by the Schaffer-collaterals (SC), originating from hippocampal CA3 neurons. Little information is available on whether and how eCBs modulate glutamatergic synaptic transmission and plasticity at PP synapses

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