Retrograde endocannabinoid signaling at striatal synapses requires a regulated postsynaptic release step

Area of Science:

• Neuroscience
• Synaptic Plasticity
• Endocannabinoid System

Background:

• Endocannabinoids (eCBs) are key retrograde messengers modulating synaptic strength.
• Previous research suggested postsynaptic eCB release, but the regulation of this process remained unclear.

Purpose of the Study:

• To investigate the conditions and regulation of eCB release from postsynaptic neurons.
• To determine if eCB release is an automatic process or actively regulated by synaptic activity.

Main Methods:

• Postsynaptic loading of medium spiny neurons (MSNs) with anandamide (AEA) or 2-arachidonoylglycerol.
• Measurement of presynaptic glutamatergic (EPSCs) and GABAergic (IPSCs) currents.
• Pharmacological manipulation including CB(1) receptor antagonists (AM251) and eCB transport blockers (VDM11, UCM707).
• Assessment of temperature dependence and requirement for various signaling molecules.

Main Results:

• Postsynaptic eCB loading induced presynaptic depression of both EPSCs and IPSCs, contingent on afferent activation levels.
• Excitatory synapse depression was temperature-dependent and blocked by eCB transport inhibitors, independent of mGluRs, Ca2+ channels, NO, or Na+ channels.
• AM251 reversed EPSC depression but not IPSC depression; direct CB(1)R activation mimicked depression independently of stimulation.

Conclusions:

• Retrograde endocannabinoid signaling necessitates a regulated postsynaptic release mechanism.
• This release involves a transporter or carrier activated by afferent/synaptic stimulation.
• The findings clarify the regulatory control over eCB-mediated synaptic plasticity.