Shedding light on left hippocampal mGlu5 in Alzheimer's disease.

Abstract

Metabotropic glutamate receptor 5 (mGlu5) is essential for synaptic plasticity and memory, making it a potential therapeutic target in Alzheimer's disease (AD). While hemispheric asymmetries in hippocampal function have been observed in AD patients, the lateralized contribution of mGlu5 signaling to cognitive decline remains unclear. Here, we show a physiological left-right asymmetry in hippocampal mGlu5 expression in wild-type mice, with higher levels in the left hemisphere, consistent with previous reports. This physiological asymmetry is lost in two distinct mouse models of AD, the J20 and 5xFAD mice, revealing a hemisphere-specific disruption of hippocampal mGlu5 regulation. Using the light-controllable negative allosteric modulator Alloswitch-1, we show that selective inhibition of left, but not right, hippocampal mGlu5 restores working and short-term memory in AD mice. This finding indicates that altered mGlu5 expression does not simply reflect receptor loss, but rather a dysregulated signaling state that remains functionally relevant and pharmacologically targetable. Left-specific modulation also normalizes pathological downstream signaling, including aberrant Pyk2 and GSK-3β activation and tau hyperphosphorylation, across both hemispheres, indicating a widespread impact of hemisphere-selective intervention. These findings establish a functional lateralization of hippocampal mGlu5 signaling and identify the left hippocampus as a critical site for mGlu5-dependent memory dysfunction in AD. They also highlight the therapeutic potential of region-specific photopharmacology for precise intervention in early AD pathology, providing a strategy for spatially targeted modulation of pathological synaptic signaling in neurodegenerative disease.