Microglia supports both the singular form of LTP expressed by the lateral perforant path and episodic memory.

Abstract

We report here that microglia exert a surprisingly discrete but functionally critical influence on synaptic plasticity in 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 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 cortico-hippocampal circuit that is critical for episodic memory.Significance Statement There has been considerable interest in microglial involvement in the moment-to-moment operations of the brain. However, the present studies show that, with one prominent exception, treatments that significantly deplete forebrain microglia have no detectable influence on synaptic operations at multiple sites within hippocampus. Nevertheless, long-term potentiation was selectively disrupted within the lateral perforant path, a primary cortical input to hippocampus. Relatedly, microglial depletion was associated with severe impairments in encoding the principal components of episodic memory. These results indicate microglial influences on synaptic transmission are surprising discrete and yet essential for orderly cognition.