Increased dendritic inhibition of dentate gyrus granule cells in a mouse model of Down syndrome

Down syndrome is the most common genetic neurodevelopmental disorder associated with mild-to-moderate intellectual disability. A disturbed excitation-inhibition balance is thought to be a major cause for the intellectual deficits in DS. In this study, we used patch-clamp electrophysiology, optogenetic stimulation and immunohistochemistry to investigate synaptic inhibition from specific interneuron subpopulations onto granule cells of the dentate gyrus in Ts65Dn mice. Optogenetically evoked inhibitory postsynaptic currents (IPSCs) from somatostatin (SOM) interneurons onto dendrites of granule cells in the outer molecular layer (ML) did not differ between euploid (Eu) and Ts65Dn mice, indicating normal distal dendritic inhibition in Ts65Dn mice. In addition, optogenetically evoked IPSCs from parvalbumin (PV) interneurons were significantly reduced, indicating reduced functional somatic inhibition in Ts65Dn mice. In contrast, activation of cholecystokinin (CCK) positive interneurons by targeted electrical microstimulation of the inner molecular layer (iML) resulted in IPSCs of increased amplitude (Eu: 372.5 ± 51.97 pA, <i>n</i> = 10; Ts65Dn: 619.9 ± 74.68 pA, <i>n</i> = 9). GABAergic synaptic terminals of CCK interneurons express cannabinoid receptor 1 (CB1). Quantitative analysis of synapses double-labeled for CB1 and the vesicular GABA transporter (VGAT) revealed a significantly increased number of putative CCK interneuron terminals in the iML of Ts65Dn mice (Eu: 0.048 ± 0.014 puncta/μm³, Ts65Dn: 0.34 ± 0.12 puncta/μm³). In contrast, the density of PV-VGAT double-positive synapses within the granule cell layer did not differ between the two genotypes. Taken together, our results indicate that proximal dendritic inhibition from CCK interneurons is increased in the dentate gyrus of Ts65Dn mice, while PV interneuron-mediated somatic inhibition appears to be unchanged or functionally diminished.