Related Experiment Video
Updated: Sep 20, 2025
Long-term Potentiation of Perforant Pathway-dentate Gyrus Synapse in Freely Behaving Mice
Published on: November 29, 2013
Microglia Support Both the Singular Form of LTP Expressed by the Lateral Perforant Path and Episodic Memory
Jasmine Chavez1, Aliza A Le1, Julian Quintanilla1
1Departments of Anatomy and Neurobiology, University of California, Irvine, California 92697.
Abstract:
We report here that microglia exert a surprisingly discrete but functionally critical influence on synaptic plasticity in the mouse hippocampus. Treatment of adult male mice with colony-stimulating factor 1 receptor antagonist PLX5622 (PLX), with resultant depletion of forebrain microglia, did not disturb basal synaptic transmission at four synaptic connections in the hippocampus. Long-term potentiation (LTP) was also intact for three of these sites, but the singular, endocannabinoid-dependent form of LTP expressed by lateral perforant path (LPP) input to the dentate gyrus (DG) was severely impaired. The LPP-LTP defect occurred in conjunction with a pronounced increase in DG (but not neocortical) levels of 2-arachidonoylglycerol (2-AG), the retrograde (spine-to-terminal) endocannabinoid messenger that initiates LPP-LTP. Despite this, concentrations of the 2-AG synthetic enzyme diacylglycerol lipase were not affected by PLX treatment. Synaptic levels of the cannabinoid type 1 receptor, which mediates 2-AG effects on LPP-LTP, were similarly unaffected. Prior work has implicated the LPP in episodic memory. We determined that the LPP-LTP impairment in PLX-treated mice was accompanied by a failure to acquire the three basic elements of an episode: the identities, locations, and presentation order for a collection of olfactory cues. Treatment with JZL184, which inhibits the 2-AG degradative enzyme monoglyceride lipase, restored both LPP-LTP and episodic "What" encoding in PLX-treated mice. We conclude that microglia selectively regulate endocannabinoid transmission at the LPP→DG synapse and thereby potently influence synaptic plasticity at the initial stage of a corticohippocampal circuit that is critical for episodic memory.
Insights
Microglia critically regulate synaptic plasticity in the hippocampus by influencing endocannabinoid signaling. Depleting microglia impairs long-term potentiation (LTP) and episodic memory, highlighting their role in brain function.
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.
Related Concept Videos
01:25Long-term Potentiation
Hebbian LTP
LTP can occur when...
01:03Long-term Depression
Calcium Ion Concentration Mechanism
If over...
01:18Long-Term Memory
Long-term memory can be categorized into two primary types: explicit and implicit memory. Explicit memory, also known as declarative memory, involves the conscious recollection of information that we deliberately try to remember, recall, and articulate. This type of memory encompasses specific facts, events, and...