A role for autophagy in long‐term spatial memory formation in male rodents

• Published in: Journal of neuroscience research 2018-03, Vol.96 (3), p.416-426
• Main Authors: Hylin, Michael J., Zhao, Jing, Tangavelou, Karthikeyan, Rozas, Natalia S., Hood, Kimberly N., MacGowan, Jacalyn S., Moore, Anthony N., Dash, Pramod K.
• Format: Article
• Language: English
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; Animal memory; Animals; Antigens, Nuclear - metabolism; Autophagy; Autophagy - drug effects; Autophagy - physiology; Beclin-1 - metabolism; Benzylamines - pharmacology; Drugs; Glial Fibrillary Acidic Protein - metabolism; hippocampus; Hippocampus - cytology; Hippocampus - drug effects; Hippocampus - metabolism; Inhibitors; Learning; Long term memory; Male; Maze learning; Maze Learning - drug effects; Maze Learning - physiology; Memory tasks; Memory, Long-Term - drug effects; Memory, Long-Term - physiology; Memory, Short-Term - drug effects; Memory, Short-Term - physiology; Mice; Microtubule-Associated Proteins - metabolism; Nerve Tissue Proteins - metabolism; Phagocytosis; Phagosomes; Phosphatidylinositol 3-Kinase - metabolism; Phosphorylation; Protein biosynthesis; Protein synthesis; Proteins; Quinazolines - pharmacology; Rapamycin; Rats; Rats, Long-Evans; Recall; Rodents; Short term; Short term memory; Spatial analysis; Spatial memory; Spatial Memory - drug effects; Spatial Memory - physiology; TOR protein; Training; water maze
• ISSN: 0360-4012; 1097-4547
• DOI: 10.1002/jnr.24121

A hallmark of long‐term memory formation is the requirement for protein synthesis. Administration of protein synthesis inhibitors impairs long‐term memory formation without influencing short‐term memory. Rapamycin is a specific inhibitor of target of rapamycin complex 1 (TORC1) that has been shown to block protein synthesis and impair long‐term memory. In addition to regulating protein synthesis, TORC1 also phosphorylates Unc‐51‐like autophagy activating kinase‐1 (Ulk‐1) to suppress autophagy. As autophagy can be activated by rapamycin (and rapamycin inhibits long‐term memory), our aim was to test the hypothesis that autophagy inhibitors would enhance long‐term memory. To examine if learning alters autophagosome number, we used male reporter mice carrying the GFP‐LC3 transgene. Using these mice, we observed that training in the Morris water maze task increases the number of autophagosomes, a finding contrary to our expectations. For learning and memory studies, male Long Evans rats were used due to their relatively larger size (compared to mice), making it easier to perform intrahippocampal infusions in awake, moving animals. When the autophagy inhibitors 3‐methyladenine (3‐MA) or Spautin‐1 were administered bilaterally into the hippocampii prior to training in the Morris water maze task, the drugs did not alter learning. In contrast, when memory was tested 24 hours later by a probe trial, significant impairments were observed. In addition, intrahippocampal infusion of an autophagy activator peptide (TAT‐Beclin‐1) improved long‐term memory. These results indicate that autophagy is not necessary for learning, but is required for long‐term memory formation. Using GFP‐LC3 transgenic mice, we provide evidence that spatial learning increases autophagosome formation in hippocampal neurons. Further, we show that intrahippocampal infusion of inhibitors of autophagy do not affect spatial learning, but impair long‐term spatial memory. In contrast, post‐training infusion of the activator of autophagy Tat‐Beclin1 peptide improves long‐term memory.