ORIGINAL RESEARCH article
Front. Cell. Neurosci.
Sec. Cellular Neuropathology
This article is part of the Research TopicInterneurons in Pathological ConditionsView all 7 articles
Increased dendritic inhibition of dentate gyrus granule cells in a mouse model of Down syndrome
Provisionally accepted
- 1Translational Epilepsy Research, Universitatsklinikum Freiburg Klinik fur Neurochirurgie, Freiburg, Germany
- 2Albert-Ludwigs-Universitat Freiburg Fakultat fur Biologie, Freiburg, Germany
- 3Albert-Ludwigs-Universitat Freiburg BrainLinks-BrainTools, Freiburg, Germany
- 4Department of Hematology and Oncology, Core Facility, Medical Center, Albert-Ludwigs-Universitat Freiburg Medizinische Fakultat, Freiburg, Germany
- 5Universitat Basel Departement Biomedizin, Basel, Switzerland
- 6F Hoffmann-La Roche AG Research and Development Division, Basel, Switzerland
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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, n=10; Ts65Dn: 619.9 ± 74.68 pA, n=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 inner ML 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.
Keywords: Dendrite, GABA, Hippocampus, inhibition, interneuron, optogenetics, patch-clamp electrophysiology, trisomy 21
Received: 27 Sep 2025; Accepted: 05 Jan 2026.
Copyright: © 2026 Gutmann, Häussler, Mersi, Follo, Bischofberger and Schulz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jan M Schulz
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