title: Dysfunctional hippocampal inhibition in the Ts65Dn mouse model of Down syndrome.
abstract: GABAergic dysfunction is implicated in hippocampal deficits of the Ts65Dn mouse model of Down syndrome (DS). Since Ts65Dn mice overexpress G-protein coupled inward-rectifying potassium (GIRK2) containing channels, we sought to evaluate whether increased GABAergic function disrupts the functioning of hippocampal circuitry. After confirming that GABA(B)/GIRK current density is significantly elevated in Ts65Dn CA1 pyramidal neurons, we compared monosynaptic inhibitory inputs in CA1 pyramidal neurons in response to proximal (stratum radiatum; SR) and distal (stratum lacunosum moleculare; SLM) stimulation of diploid and Ts65Dn acute hippocampal slices. Synaptic GABA(B) and GABA(A) mediated currents evoked by SR stimulation were generally unaffected in Ts65Dn CA1 neurons. However, the GABA(B)/GABA(A) ratios evoked by stimulation within the SLM of Ts65Dn hippocampus were significantly larger in magnitude, consistent with increased GABA(B)/GIRK currents after SLM stimulation. These results indicate that GIRK overexpression in Ts65Dn has functional consequences which affect the balance between GABA(B) and GABA(A) inhibition of CA1 pyramidal neurons, most likely in a pathway specific manner, and may contribute to cognitive deficits reported in these mice.
authors.affiliation: Neuroscience Graduate Program, Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, School of Medicine, Bethesda, MD 20814, USA.
authors.forename: Tyler K
authors.initials: TK
authors.lastname: Best
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Cramer
authors.forename: Lina
authors.initials: L
authors.lastname: Chakrabarti
authors.forename: Tarik F
authors.initials: TF
authors.lastname: Haydar
authors.forename: Zygmunt
authors.initials: Z
authors.lastname: Galdzicki
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000502:physiology*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000503:physiopathology*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000096:biosynthesis / Q000235:genetics; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000235:genetics*; D009924:Organ Culture Techniques; D011963:Receptors, GABA-A / Q000502:physiology; D018080:Receptors, GABA-B / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C094401:KCNJ6 protein, human; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B