Inhibiting Hippo pathway kinases releases WWC1 to promote AMPAR-dependent synaptic plasticity and long-term memory in mice

Abstract

The localization, number, and function of postsynaptic AMPA-type glutamate receptors (AMPARs) are crucial for synaptic plasticity, a cellular correlate for learning and memory. The Hippo pathway member WWC1 is an important component of AMPAR-containing protein complexes. However, the availability of WWC1 is constrained by its interaction with the Hippo pathway kinases LATS1 and LATS2 (LATS1/2). Here, we explored the biochemical regulation of this interaction and found that it is pharmacologically targetable in vivo. In primary hippocampal neurons, phosphorylation of LATS1/2 by the upstream kinases MST1 and MST2 (MST1/2) enhanced the interaction between WWC1 and LATS1/2, which sequestered WWC1. Pharmacologically inhibiting MST1/2 in male mice and in human brain-derived organoids promoted the dissociation of WWC1 from LATS1/2, leading to an increase in WWC1 in AMPAR-containing complexes. MST1/2 inhibition enhanced synaptic transmission in mouse hippocampal brain slices and improved cognition in healthy male mice and in male mouse models of Alzheimer’s disease and aging. Thus, compounds that disrupt the interaction between WWC1 and LATS1/2 might be explored for development as cognitive enhancers.

Abstract

Blocking its sequestration by Hippo pathway kinases shifts WWC1 to neuroreceptors that promote learning.

Editor’s summary

The scaffolding protein WWC1 facilitates signaling through the Hippo pathway and promotes synaptic plasticity that underlies learning and memory. Stepan et al . found that blocking Hippo signaling improved cognition in mice by enabling the redistribution of WWC1. In hippocampal neurons, WWC1 was bound to Hippo pathway kinases. Blocking the activation of these kinases released WWC1 to interact with AMPA-type glutamate receptor complexes. This treatment improved cognitive performance in aged and Alzheimer’s disease model mice, revealing that targeting Hippo pathway kinases may have potential for therapeutic development. —Leslie K. Ferrarelli