In mouse models of Down syndrome (DS), cognitive deficits such as memory impairment are believed to be caused by overinhibition. However, recent studies indicate that the overexpression of Grik1, a gene mainly expressed at interneurons in the hippocampus, could be a key driver of memory deficits in individuals with DS due to a bidirectional alteration of synaptic inhibition on CA1 pyramidal cells (Valbuena et al, Nature Comms. 2019, 10:4991). Remarkably, normalizing Grik1 dosage in the Ts2Cje mouse model of DS specifically restores spatial memory and reverses the bidirectional alterations to CA1 inhibition. Grik1 is strongly expressed in most of the Oriens-Lacunosum Moleculare (OLM) neurons, which specifically inhibit distal dendrites of CA1 pyramidal cells, leading us to hypothesize that overexpression of this gene in this particular set of neurons may drive strong inhibition of temporoammonic inputs to CA1, ultimately altering the formation of memory engrams. To test this hypothesis, we conducted experiments in mice where the dose of Grik1 was genetically manipulated in this neuronal population. Our results provide compelling evidence that the overexpression of Grik1 in OLM neurons plays a key role in the cognitive deficits observed in mouse models of DS. By identifying the specific mechanisms that underlie overinhibition in DS, our study highlights potential new therapeutic targets for treating cognitive impairment in individuals with this condition.