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  • Occupying at least of brain volume astroglial cells not

    2021-09-15

    Occupying at least 50% of DGAT-1 inhibitor volume, astroglial cells not only possess a high level of association in network through gap junctions and direct intercellular communications [28], but also are extensively exposed to extracellular fluid and contribute in shaping different types of synapses [29]. Our recent findings of astroglial CB1R [8] imply the existence of extracellular eCBs that are able to directly activate astroglial CB1R. This notion is supported by consistent in vivo microdialysis reports of baseline levels of extracellular AEA in the brain [30], [31], [32]. After a systemic injection, the FAAH inhibitor URB597 or PF3845 produced a significant increase of extracellular levels of AEA but not 2-AG [30], [31], [32], while mutant mice with a selective deletion of FAAH gene prominently increased extracellular concentrations of AEA [31]. These lines of evidence strongly support the idea that hippocampal extracellular AEA forms a basal AEA stream, similar to hippocampal extracellular 2-AG stream [8], with both a continuous supply from unknown resources and a constant clearance by FAAH. Thus, an acute suppression of FAAH by PF3845 results in an acute accumulation of extracellular AEA, activating astroglial CB1R. Recently, we observed that both exogenous cannabinoids and the eCB 2-AG could activate hippocampal astroglial CB1R to elicit in vivo LTD at glutamatergic CA3-CA1 synapses [8], [9]. Accordingly, our above findings indicate the possibility that PF3845 produces antidepressant effects through increase of brain AEA levels to activate brain astroglial CB1R, leading to in vivo LTD production at CA3-CA1 synapses. To examine this working hypothesis, we examined whether Tat-GluR2 peptide is able to abolish PF3845-induced antidepressant effects. The expression of glutamate NMDA receptor-mediated LTD requires facilitated endocytosis of postsynaptic AMPA receptor [33]. The administration of the brain-penetrating version of Tat-GluR2 peptide able to block AMPA receptor endocytosis, but not of its scrambled analogue (Tat-GluR2s) [33], specifically blocked exogenous cannabinoids- and 2-AG-elicited LTD expression at CA3-CA1 synapses [8], [9]. We indeed found that either systemic or intra-CA1 administration of Tat-GluR2, but not Tat-GluR2s, abolished PF3845-induced antidepressant effects. Administration of RNA transcription (actinomycin-d, 72mg/12ml, i.c.v.) 2h before AEA injection selectively reversed the late-phase expression of CB-LTD. The maintenance of late-phase LTD, but not early-phase LTD or transient synaptic transmission depression, requires new protein synthesis. Collectively, these findings strongly suggest that PF3845 increases levels of AEA, which activates astroglial CB1R to induce in vivo LTD at CA3-CA1 synapses, resulting in antidepressant effects in naïve mice in response to acute stress (Fig. 6). This idea is supported by our further observation that either systemic administration of PF3845 or intra-CA1 microinjection of AEA into naïve mice or rats induced in vivo LTD at CA3-CA1 synapses, which was prevented by AM281 and Tat-GluR2. Our recent study clearly suggests that depression-like behavior of acute or chronic CORT-exposed mice results from enhancement or suppression of CA1 pyramidal neurons, respectively [9]. After identification of PF3845-elicited antidepressant effects in naïve animals in response to acute stress, we investigated whether PF3845 was able to produce antidepressant effects in chronic CORT-exposed mice. Chronic oral exposure of rodents to the stress hormone CORT induced persistent and long-lasting depression-like behavior that could be reversed with chronic, but not sub-chronic, administration of conventional antidepressants [34]. Therefore, this rodent model closely mimics clinical major depression [9]. Anhedonia, i.e. loss of pleasure, is one of the core symptoms of patients with major depression [35]. The MAGL inhibitor JZL184 (5mg/kg, i.p.) prevented acute stress-induced decrease of sucrose consumption in naïve animals, i.e., anti-anhedonia behavioral response, likely through induction of LTD at CA3-CA1 synapses [9]. However, the same dose of JZL184 did not produce significant anti-anhedonia effects in chronic CORT-exposed mice[9]. In the present study, we observed that PF3845 (10mg/kg, i.p.), DGAT-1 inhibitor which produced antidepressant effects in naïve animals in response to acute stress, did not produce significant anti-anhedonia effects in chronic CORT-exposed mice.