Dysfunction of GABAergic interneurons during sensitive time windows plays a crucial role in the etiopathogenesis of neurodevelopmental disorders. GABAergic transmission through Cl-permeable GABAA receptors (GABAAR) is depolarizing in pyramidal neurons of the CA1 region of the hippocampus of the Ts65Dn mouse model of Down syndrome. This depends on the upregulation of the Cl-importer NKCC1 and leads to an impairment of synaptic plasticity and memory in Ts65Dn adult mice. Accordingly, inhibiting NKCC1 rescues the Ts65Dn phenotype. However, the contribution of specific interneuron subpopulations to the Ts65Dn mice deficits is largely unknown.We characterized parvalbumin (PV) and somatostatin (SOM)-positive interneurons in the hippocampus of 3-months-old Ts65Dn mice versus control littermates by immunohistochemistry and electrophysiological recordings on brain slices. Ts65Dn mice showed fewer PV interneurons and lower expression of their perineuronal nets in the stratum pyramidale and dentate gyrus of hippocampus. Ts65Dn PV neurons showed higher membrane time constant, wider action potentials, lower action potential frequency, and their excitatory/inhibitory balance was shifted towards inhibition. Differently, Ts65Dn SOM interneurons were reduced in the CA1 region and showed lower membrane time constant, higher action potential threshold and higher action potential frequency. LTP experiments on hippocampal slices from Ts65Dn mice expressing inhibitory DREADDs in SOM interneurons showed that diminishing their activity rescued synaptic plasticity, with no effect on controls.Our results suggest that PV neurons have a defective neurogenesis and maturation, whereas SOM neurons are hyperexcitable. This concurs to the defective hippocampal information-processing of Ts65Dn mice and interneuron manipulation holds promise as a future therapeutic strategy.