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

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.