The MAP6-NTS axis in hippocampal CA1 regulates synaptic plasticity and memory

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Microtubule-associated Protein 6 (MAP6) is essential for microtubule stability and synaptic plasticity.
• MAP6 dysfunction is linked to cognitive impairment, but underlying mechanisms are unclear.

Purpose of the Study:

• To investigate the molecular mechanisms by which MAP6 deletion leads to cognitive deficits.
• To identify potential therapeutic targets for MAP6-associated cognitive impairment.

Main Methods:

• Generated Map6 knockout (KO) mice using CRISPR/Cas9.
• Conducted behavioral tests for cognitive assessment.
• Performed hippocampal transcriptome profiling, mRNA/protein validation, and rescue experiments with neurotensin (NTS).
• Utilized electrophysiology and chemogenetics to assess synaptic function and neuronal activity.

Main Results:

• Map6^-/- mice showed significant long-term memory and spatial learning deficits.
• Hippocampal transcriptome analysis revealed downregulation of neurotensin (NTS) in Map6^-/- mice.
• NTS administration rescued cognitive deficits and restored long-term potentiation (LTP) in Map6^-/- mice.
• Chemogenetic activation of CA1^Nts neurons reversed synaptic and behavioral deficits.

Conclusions:

• MAP6 deletion impairs cognitive function by suppressing hippocampal NTS expression and secretion.
• Exogenous NTS supplementation and NTS signaling activation can reverse MAP6 deletion-induced cognitive and synaptic deficits.
• NTS is identified as a critical downstream effector of MAP6 in cognitive regulation, presenting a potential therapeutic target.