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Subsequent investigations in conditional knockout mice revealed the involvement of CB1R in GABAergic neurons, but not those in glutamatergic neurons or astrocytes, in this overgeneralization. In addition, activation of GABA\n                    <jats:sub>A<\/jats:sub>\n                    receptors on pyramidal neurons was required for inducing overgeneralization via AM281, a CB1R antagonist. Neural mechanistic studies showed that eCBs\/CB1R signaling regulates both the activity and plasticity of inhibitory synapses during generalization, highlighting the prominence of the disinhibition of CB1R in interneurons during this process. Subsequently, we delved into the downstream effects and found that eCB-dependent long-term potentiation (LTP) in CA1 pyramidal neurons was regulated by the aforementioned mechanisms. Our findings illustrate that the eCBs\/CB1R signaling pathway modulates the balance between fear memory discrimination and generalization by controlling inhibitory inputs to hippocampal pyramidal neurons, accompanied by alterations in excitatory plasticity within this region.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2423974122","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T16:26:02Z","timestamp":1754411162000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":6,"title":["Endocannabinoids inhibit contextual fear memory generalization via hippocampal GABAergic synaptic transmission"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8101-1064","authenticated-orcid":false,"given":"Qian","family":"Ge","sequence":"first","affiliation":[{"name":"Key Laboratory of Modern Teaching Technology, Ministry of Education, Shaanxi Normal 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