Abstract

Microtubule-associated Protein 6 (MAP6) is critical for maintaining microtubule stability and synaptic plasticity, and its dysfunction is a key driver of cognitive impairment. However, the molecular mechanisms linking MAP6 deletion to cognitive deficits remain unclear. Here, we generated a novel Map6 knockout (KO, Map6 −/− ) mouse model using CRISPR/Cas9-mediated genome editing. Behavioral tests confirmed that Map6 −/− mice exhibited prominent cognitive impairments, primarily in long-term memory and spatial learning. Hippocampal transcriptome profiling identified marked downregulation of neurotensin ( Nts ) in Map6 −/− mice, which was validated at both mRNA and protein levels. Rescue experiments demonstrated that direct microinjection of neurotensin (NTS) peptide into the hippocampal CA1 subregion significantly improved cognitive deficits in Map6 −/− mice. Electrophysiological recordings further confirmed that NTS restored impaired long-term potentiation (LTP)—a cellular substrate of learning and memory—in the hippocampal CA1 of Map6 −/− mice. Additionally, chemogenetic activation of CA1 NTS-positive (CA1 Nts ) neurons reversed these synaptic and behavioral phenotypes. Collectively, we delineate a novel pathway wherein MAP6 deletion induces cognitive impairment by suppressing hippocampal NTS expression and secretion, and both exogenous NTS supplementation and NTS signaling activation reverse Map6 deletion-induced synaptic and behavioral deficits. These findings identify NTS as a critical downstream effector of MAP6 in cognitive regulation, offering a potential therapeutic target for cognitive impairment.