Endocannabinoids Differentially Modulate Synaptic Plasticity in Rat Hippocampal CA1 Pyramidal Neurons

PLOS ONE, Apr 2010

Background 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. 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 Findings By 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/Significance Our 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.

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Endocannabinoids Differentially Modulate Synaptic Plasticity in Rat Hippocampal CA1 Pyramidal Neurons

Chen C (2010) Endocannabinoids Differentially Modulate Synaptic Plasticity in Rat Hippocampal CA1 Pyramidal Neurons. PLoS ONE 5(4): e10306. doi:10.1371/journal.pone.0010306 Endocannabinoids Differentially Modulate Synaptic Plasticity in Rat Hippocampal CA1 Pyramidal Neurons Jian-Yi Xu 0 Rongqing Chen 0 Jian Zhang 0 Chu Chen 0 Olivier Jacques Manzoni, INSERM U862, France 0 Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center , New Orleans, Louisiana , United States of America Background: 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. 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 Findings: By 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/Significance: Our 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. - Funding: This work was supported by National Institutes of Health grant NS054886 and DA025971. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. 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. The information from the CA3 neurons through the SC originates from layer II neurons of the entorhinal cortex and is relayed through synapses onto granule neurons in the detate gyrus and pyramidal neurons in the CA3 region [1,2]. The dual sensory inputs that the CA1 pyramidal neurons receive have been suggested to be essential for information processing, consolidation, storage and retrieval in the hippocampus [36]. For instance, it has been demonstrated that direct cortical input to CA1 through the PP pathway is required for long-term memory and plasticity [4,6,7]. LTP or LTD-inducing stimulation at the PP has been shown to modulate synaptic plasticity of the SC [5,8,9]. Recent evidence also shows that pairing of PP and SC inputs induces an input-timing-dependent plasticity of the SC in CA1 pyramidal neurons, indicating that interactions of distal PP and proximal synaptic inputs occur in the same CA1 pyramidal neurons [10]. Available evidence shows differences in expression and function of ion channels and receptors at synapses of CA1 pyramidal neurons between SLM and SR regions [4,1116]. The PP and SC also exhibit distinct synaptic responses to neurotransmitters or modulators [1720], suggesting that synaptic activity at the PP and SC is differentially modulated by neurotransmitters. Endocannabinoids (eCBs), naturally occurring lipid mediators, are involved in a variety of physiological, pharmacological, and pathological processes [2123]. While t (...truncated)


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Jian-Yi Xu, Rongqing Chen, Jian Zhang, Chu Chen. Endocannabinoids Differentially Modulate Synaptic Plasticity in Rat Hippocampal CA1 Pyramidal Neurons, PLOS ONE, 2010, 4, DOI: 10.1371/journal.pone.0010306