Microglia Support Both the Singular Form of LTP Expressed by the Lateral Perforant Path and Episodic Memory

Area of Science:

• Neuroscience
• Cell Biology
• Synaptic Plasticity

Background:

• Microglia, the resident immune cells of the brain, are increasingly recognized for their roles beyond immunity.
• Synaptic plasticity, the ability of synapses to strengthen or weaken over time, is crucial for learning and memory.
• Endocannabinoids are key retrograde messengers involved in modulating synaptic plasticity, particularly in the hippocampus.

Purpose of the Study:

• To investigate the specific role of microglia in regulating synaptic plasticity in the mouse hippocampus.
• To determine the impact of microglial depletion on endocannabinoid signaling and long-term potentiation (LTP).
• To assess the consequences of microglial-mediated synaptic changes on episodic memory formation.

Main Methods:

• Adult male mice were treated with colony-stimulating factor 1 receptor antagonist PLX5622 (PLX) to deplete forebrain microglia.
• Basal synaptic transmission and LTP were measured at hippocampal synapses, including the lateral perforant path (LPP) input to the dentate gyrus (DG).
• Levels of 2-arachidonoylglycerol (2-AG) and cannabinoid type 1 receptor were quantified; episodic memory was assessed using olfactory cue tasks.

Main Results:

• Microglial depletion did not affect basal synaptic transmission or LTP at most hippocampal synapses.
• A specific form of endocannabinoid-dependent LTP at the LPP→DG synapse was severely impaired in PLX-treated mice.
• Impaired LPP-LTP correlated with increased DG 2-AG levels and deficits in encoding episodic memory ('What', 'Where', 'When').

Conclusions:

• Microglia selectively regulate endocannabinoid transmission at the LPP→DG synapse.
• This microglial regulation of endocannabinoids is critical for synaptic plasticity underlying episodic memory.
• Targeting microglia may offer a novel therapeutic strategy for memory disorders.