Deficits in Cognition and Synaptic Plasticity in a Mouse Model of Down Syndrome Ameliorated by GABAB Receptor Antagonists

Abstract

Cognitive impairment in Down syndrome (DS) is characterized by deficient learning and memory. Mouse genetic models of DS exhibit impaired cognition in hippocampally mediated behavioral tasks and reduced synaptic plasticity of hippocampal pathways. Enhanced efficiency of GABAergic neurotransmission was implicated in those changes. We have recently shown that signaling through postsynaptic GABAB receptors is significantly increased in the dentate gyrus (DG) of Ts65Dn mice, a genetic model of DS. Here we examined a role for GABAB receptors in cognitive deficits in DS by defining the effect of selective GABAB receptor antagonists on behavior and synaptic plasticity of adult Ts65Dn mice. Treatment with the GABAB receptor antagonist CGP55845 restored memory of Ts65Dn mice in the novel place recognition, novel object recognition and contextual fear conditioning tasks, but did not affect locomotion and performance in T-maze. The treatment increased hippocampal levels of brain-derived neurotrophic factor (BDNF), equally in 2N and Ts65Dn mice. In hippocampal slices, treatment with the GABAB receptor antagonists CGP55845 or CGP52432 enhanced long-term potentiation (LTP) in the Ts65Dn DG. The enhancement of LTP was accompanied by an increase in the NMDA receptor-mediated component of the tetanus-evoked responses. These findings are evidence for a contribution of GABAB receptors to changes in hippocampal-based cognition in the Ts65Dn mouse. The ability to rescue cognitive performance through treatment with selective GABAB receptor antagonists motivates studies to further explore the therapeutic potential of these compounds in people with DS.

Systemic Lipopolysaccharide Administration-Induced Cognitive Impairments are Reversed by Erythropoietin Treatment in Mice

“…In support with this hypothesis, LPS has been demonstrated to impair longterm potentiation, a key cellular process of learning and memory consolidation [28,29]. It has been previously demonstrated that LPS reduces hippocampal mRNA levels of BDNF, a neurotrophin that plays an important role in learning and memory processes [29].…”

“…Synaptic transmission is essential for nervous system function, and its dysfunction is a known major contributing factor to cognitive impairments [28]. In support with this hypothesis, LPS has been demonstrated to impair longterm potentiation, a key cellular process of learning and memory consolidation [28,29].…”

16p11.2 Deletion mice display cognitive deficits in touchscreen learning and novelty recognition tasks

“…Novel object recognition and object location memory both assess the ability to recognize novelty in the environment, relevant to recognition abilities that are critical for territorial defense and foraging in rodents (Sutcliffe et al 2007). Impairments in these tasks may be analogous to aspects of intellectual disabilities in humans (Kleschevnikov et al 2012;Smith et al 2014). However, it is important to note our previous finding that housing 16p11.2 mice in same-genotype cages resulted in normal performance on novel object recognition and object location memory (Yang et al 2015a), highlighting the importance of evaluating environmental factors as modulators of behavioral phenotypes in genetic models.…”

Altered Distribution of Hippocampal Interneurons in the Murine Down Syndrome Model Ts65Dn

“…Additionally, other studies have observed and excess of GABA release in trisomic mice [53]. Other studies have observed also a higher sensitivity of inhibition, as a consequence of changes in GABA receptors and in potassium channels [27,54,55] therefore increasing the inhibition of the system. In short, different reports point to more inhibitory contacts and more efficient ones.…”