title: Increased efficiency of the GABAA and GABAB receptor-mediated neurotransmission in the Ts65Dn mouse model of Down syndrome.
abstract: Cognitive impairment in Down syndrome (DS) involves the hippocampus. In the Ts65Dn mouse model of DS, deficits in hippocampus-dependent learning and synaptic plasticity were linked to enhanced inhibition. However, the mechanistic basis of changes in inhibitory efficiency remains largely unexplored, and efficiency of the GABAergic synaptic neurotransmission has not yet been investigated in direct electrophysiological experiments. To investigate this important feature of neurobiology of DS, we examined synaptic and molecular properties of the GABAergic system in the dentate gyrus (DG) of adult Ts65Dn mice. Both GABAA and GABAB receptor-mediated components of evoked inhibitory postsynaptic currents (IPSCs) were significantly increased in Ts65Dn vs. control (2N) DG granule cells. These changes were unaccompanied by alterations in hippocampal levels of GABAA (α1, α2, α3, α5 and γ2) or GABAB (Gbr1a and Gbr1b) receptor subunits. Immunoreactivity for GAD65, a marker for GABAergic terminals, was also unchanged. In contrast, there was a marked change in functional parameters of GABAergic synapses. Paired stimulations showed reduced paired-pulse ratios of both GABAA and GABAB receptor-mediated IPSC components (IPSC2/IPSC1), suggesting an increase in presynaptic release of GABA. Consistent with increased gene dose, the level of the Kir3.2 subunit of potassium channels, effectors for postsynaptic GABAB receptors, was increased. This change was associated with enhanced postsynaptic GABAB/Kir3.2 signaling following application of the GABAB receptor agonist baclofen. Thus, both GABAA and GABAB receptor-mediated synaptic efficiency is increased in the Ts65Dn DG, thus likely contributing to deficient synaptic plasticity and poor learning in DS.
authors: Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. akleschevnikov@yahoo.com
authors: Alexander M
authors: AM
authors: Kleschevnikov
authors: Pavel V
authors: PV
authors: Belichenko
authors: Jessica
authors: J
authors: Gall
authors: Lizzy
authors: L
authors: George
authors: Rachel
authors: R
authors: Nosheny
authors: Michael T
authors: MT
authors: Maloney
authors: Ahmad
authors: A
authors: Salehi
authors: William C
authors: WC
authors: Mobley
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018891:Dentate Gyrus / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000378:metabolism / Q000503:physiopathology*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000096:biosynthesis; D007150:Immunohistochemistry; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D051379:Mice; D018408:Patch-Clamp Techniques; D011963:Receptors, GABA-A / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B