Abstract
Down syndrome (DS) is a genetic disorder caused by the presence of a third copy of chromosome 21. DS affects multiple organs, but it invariably results in altered brain development and diverse degrees of intellectual disability. A large body of evidence has shown that synaptic deficits and memory impairment are largely determined by altered GABAergic signaling in trisomic mouse models of DS. These alterations arise during brain development while extending into adulthood, and include genesis of GABAergic neurons, variation of the inhibitory drive and modifications in the control of neural-network excitability. Accordingly, different pharmacological interventions targeting GABAergic signaling have proven promising preclinical approaches to rescue cognitive impairment in DS mouse models. In this review, we will discuss recent data regarding the complex scenario of GABAergic dysfunctions in the trisomic brain of DS mice and patients, and we will evaluate the state of current clinical research targeting GABAergic signaling in individuals with DS.
Highlights
Down syndrome (DS) or trisomy 21 is the leading cause of genetically-defined intellectual disability and congenital birth defects
Prompted by the effectiveness of PTZ treatment and by the observation that mice knock-out for the GABAAR α5 subunit—which is highly expressed in the hippocampus (Wisden et al, 1992)—show increased learning and memory performance (Collinson et al, 2002), a second series of studies has evaluated the efficacy of two inverse agonists selective for the α5 subunit of the GABAAR and acting as negative allosteric modulators
We evaluated the evidence pointing at a role for abnormal signaling from GABAA and GABAB receptors in the neuronal defects associated with DS, and we considered the Ts65Dn mouse model of DS, one of the most largely used
Summary
Reviewed by: Enrico Cherubini, Scuola Internazionale di Studi Superiori Avanzati (SISSA), Italy. A large body of evidence has shown that synaptic deficits and memory impairment are largely determined by altered GABAergic signaling in trisomic mouse models of DS. These alterations arise during brain development while extending into adulthood, and include genesis of GABAergic neurons, variation of the inhibitory drive and modifications in the control of neural-network excitability. Different pharmacological interventions targeting GABAergic signaling have proven promising preclinical approaches to rescue cognitive impairment in DS mouse models. We will discuss recent data regarding the complex scenario of GABAergic dysfunctions in the trisomic brain of DS mice and patients, and we will evaluate the state of current clinical research targeting GABAergic signaling in individuals with DS
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