Small drug-like molecule boosts memory in mice by targeting the integrated stress response, UCSF researchers report
Researchers at UCSF have identified a small, drug-like molecule that significantly improves memory in healthy mice by acting on a conserved cellular pathway that responds to biological stress. The discovery suggests that the same biochemical route — centered on the protein eIF2α and known as the integrated stress response (ISR) — could eventually be targeted to enhance memory in humans.
The molecule, named ISRIB (integrated stress response inhibitor), was selected from a screen of roughly 100,000 small molecules at UCSF’s Small Molecule Discovery Center. The screen sought chemicals that could modulate a protective cellular program activated when cells struggle to fold newly made proteins. Follow-up experiments revealed that ISRIB acts more broadly by countering the effects of eIF2α inactivation, the key molecular switch of the ISR.
In behavioral tests, mice receiving ISRIB injections located a submerged platform in a spatial memory task about three times faster than control animals, indicating improved learning and memory consolidation. In separate fear-conditioning tests, ISRIB-treated mice more strongly remembered cues associated with an aversive stimulus, demonstrating enhanced retention of emotionally salient memories.
Mechanistically, different forms of cellular stress — accumulation of unfolded proteins, ultraviolet damage to DNA, amino acid shortage, viral infection or iron deprivation — activate distinct enzymes that converge on eIF2α. Phosphorylation of eIF2α reduces general protein synthesis, a response that conserves resources and helps cells manage stress, but it also suppresses the production of many proteins needed for memory formation. At the same time, eIF2α phosphorylation selectively increases translation of a small subset of stress-response proteins. By opposing eIF2α inactivation, ISRIB appears to release the translational brake and favor the protein synthesis needed for memory consolidation.
“Evolution has not necessarily optimized memory consolidation for maximal performance,” said Peter Walter, PhD, professor of biochemistry and biophysics at UCSF and senior author on the study. “Our findings indicate that pharmacologically modulating the integrated stress response can enhance memory in otherwise healthy animals.”
ISRIB displays favorable drug-like properties in mice: it crosses the blood–brain barrier readily, shows useful pharmacokinetics, and produces no obvious acute toxicity in the dosing paradigms tested. These attributes make ISRIB a valuable tool compound for preclinical studies of cognition and a plausible starting point for medicinal chemistry efforts aimed at developing related molecules suitable for human testing.
Co-author Nahum Sonenberg, PhD (McGill University), had previously linked eIF2α signaling to memory through genetic studies in mice; his laboratory contributed the behavioral testing described in this work. UCSF postdoctoral fellow Carmela Sidrauski, PhD, led the molecular studies that clarified how the small molecule reverses the translational effects of eIF2α phosphorylation.
Beyond applications for enhancing cognition, the team notes that manipulating the unfolded protein response and the ISR may have therapeutic potential in other areas. Cancer cells frequently exploit stress-response pathways to support survival and growth, so ISR-modulating compounds could inform new anti-cancer strategies. The investigators are exploring these possibilities while also seeking collaborators to test ISRIB and related compounds in mouse models of neurodegenerative disease and aging.
At a fundamental level, ISRIB provides scientists a powerful tool to probe how the unfolded protein response and the integrated stress response influence physiology, neural plasticity and disease processes. The work highlights the interplay between cellular stress signaling and higher-order brain functions such as learning and memory.
Notes about this neurobiology and memory research
Additional UCSF authors include Diego Acosta-Alvear, PhD; Punitha Vedantham, PhD; Brian Hearn, PhD; Ciara Gallagher, PhD; Kenny Ang, PhD; Chris Wilson, PhD; Voytek Okreglak, PhD; Byron Hann, MD, PhD; Michelle Arkin, PhD; and Adam Renslo, PhD. Contributors from other institutions include Han Li, PhD, and Avi Ashkenazi, PhD (Genentech), and Karim Nader, PhD, Karine Gamache, and Arkady Khoutorsky, PhD (McGill University).
The study was funded by the Howard Hughes Medical Institute.
Contact: Jeffrey Norris – UCSF
Source: UCSF press release
Image source: NIH (public domain)
Original research: Sidrauski C, Acosta-Alvear D, Khoutorsky A, Vedantham P, Hearn BR, Li H, Gamache K, Gallagher C, Ang KKH, Wilson C, Okreglak V, Ashkenazi A, Hann B, Nader K, Arkin MR, Renslo AR, Sonenberg N, Walter P. “Pharmacological brake-release of mRNA translation enhances cognitive memory.” eLife. Published online May 28, 2013. DOI: 10.7554/eLife.00498