Endocannabinoids differentially modulate synaptic plasticity in rat hippocampal CA1 pyramidal neurons

Area of Science:

• Neuroscience
• Synaptic Plasticity
• Cellular Electrophysiology

Background:

• Hippocampal CA1 pyramidal neurons receive distinct glutamatergic inputs from the entorhinal cortex (perforant path, PP) and CA3 neurons (Schaffer collaterals, SC).
• Endocannabinoids (eCBs) modulate synaptic transmission and plasticity via CB1 receptors, but their role at PP synapses is largely unexplored.
• Previous research primarily focused on eCB modulation of SC pathways in CA1 neurons.

Purpose of the Study:

• To investigate the role of endocannabinoids in modulating glutamatergic synaptic transmission and plasticity at perforant path (PP) synapses.
• To compare eCB-mediated plasticity at PP synapses with that at Schaffer collateral (SC) synapses in the same hippocampal CA1 pyramidal neurons.
• To elucidate the involvement of CB1 receptors in differential synaptic plasticity between PP and SC inputs.

Main Methods:

• Somatic and dendritic patch-clamp recordings in hippocampal slices.
• Calcium (Ca2+) uncaging experiments to assess intracellular calcium dynamics.
• Immunostaining to identify cellular and synaptic markers.
• Pharmacological manipulation using CB1 receptor antagonists and agonists (WIN55212).
• Genetic deletion of CB1 receptors.

Main Results:

• Significant differences in long-term depression (LTD) induced by low-frequency stimulation or DHPG were observed between PP and SC synapses.
• CB1 receptor antagonism or deletion abolished these differences, indicating CB1 receptor-dependent mechanisms.
• Depolarization-induced suppression of excitation (DSE) and Ca2+-induced suppression of EPSCs were less pronounced at PP synapses compared to SC synapses.
• WIN55212 application caused greater inhibition of EPSCs at SC synapses than at PP synapses.

Conclusions:

• CB1 receptor-dependent LTD and DSE are differentially expressed at PP versus SC synapses in hippocampal CA1 pyramidal neurons.
• These distinct plasticity mechanisms at different input sites may influence synaptic scaling, integration, and overall plasticity of CA1 neurons.
• Findings highlight a novel layer of regulation in hippocampal information processing mediated by endocannabinoids.