Shedding light on left hippocampal mGlu5 in Alzheimer’s disease

Metabotropic glutamate receptor 5 (mGlu5) plays a central role in synaptic plasticity and memory, and has emerged as a potential therapeutic target in Alzheimer’s disease (AD). While asymmetries in hippocampal function have been observed in AD patients, the lateralized contribution of mGlu5 signaling to cognitive decline remains unclear. Here, we show the presence of a physiological left-right asymmetry in mGlu5 expression in the hippocampus of wild-type mice, with higher levels in the left hemisphere, consistent with previous observations. Importantly, we reveal that this asymmetry is lost in J20 AD model mice due to a selective reduction of mGlu5 in the left hippocampus. Then, using the light-controllable negative allosteric modulator Alloswitch-1, we demonstrate that selective inhibition of mGlu5 in the left, but not right, hippocampus is both necessary and sufficient to restore working and short-term memory in J20 mice. This left-specific modulation also reverses downstream pathological signaling, including aberrant Pyk2 and GSK3-β activation and tau hyperphosphorylation, in both hippocampi. Our findings identify a functional lateralization of mGlu5 in hippocampal circuits and highlight the potential of spatially targeted photopharmacology for precise intervention in early AD pathology.