The glutamatergic receptor mGlu5, being a modulator of neurotransmission in regions such as the cortex and hippocampus, plays a crucial role in learning and memory processing. Numerous studies highlight the alteration, contribution, and potential therapeutic targeting of mGlu5 in Alzheimer disease (AD). AD is the first cause of dementia, resulting in significant cognitive deficits, including memory loss due to the accumulation of Aβ, hyperphosphorylated tau, and neurodegeneration. In patients, brain asymmetric alterations, as Aβdepositions more pronounced in the left side, are reported early in the disease, and correlated with cognitive impairment. Electrophysiological studies in rodents showed that Aβ exposure on brain slices preferentially affects left hippocampal CA3-CA1 synapses by enhancing LTD in a mGlu5 dependent way. By the use of different tools as photoswitchable drugs, we studied mGlu5 hippocampal asymmetry and how it contributes to memory deficit in AD mice. We showed that wild-type mice exhibited more abundant mGlu5 expression in their left hippocampus compared to the right. In the J20 mice model of AD, a decreased expression of hippocampal mGlu5 was observed specifically in the left hippocampus suggesting that the hippocampal asymmetry tends to diminish in these mice. Then, thanks to the fine spatial control of photoswitchable mGlu5 ligands, we observed in AD mice, a lateralized involvement of hippocampal mGlu5 in restoring spatial short memory. This study also highlights the crucial role of photopharmacology to finely manipulate endogenous modulatory mechanisms in vivo and decipher complex processes as memory impairment in AD mice.