Effects of positive allosteric modulation on electrophysiological properties of GABAAR signaling in Ts65Dn mice and induced pluripotent stem cell-derived neurons from persons with Down syndrome

Abstract

Down syndrome (DS) is the most frequent cause of genetically defined intellectual disability, which results from the presence of an extra copy of chromosome 21. A wide range of neurological phenotypes is typically observed in persons with DS, including an increased incidence of seizure disorders. Mouse models of DS, particularly Ts65Dn mice, and emerging translational approaches, such as trisomy 21 human induced pluripotent stem cells (T21-iPSCs), represent essential tools for studying and understanding the pathophysiology of DS co-morbidities. As recently reported, the hippocampus of Ts65Dn mice showed an intracellular accumulation of chloride as a result of increased hippocampal expression of the NKCC1 cotransporter, which led to the reversal of GABAAR responses from inhibitory to excitatory. In this context, positive allosteric modulators of GABAAR, such as benzodiazepines (BZDs), which act by enhancing GABA signaling, might produce paradoxical effects that may aggravate rather than ameliorate clinical conditions associated with increased neuronal excitability, such as seizure disorder. Therefore, the aim of the present study is to investigate the effects of BZDs on electrophysiological properties of GABAAR signaling in Ts65Dn mice and human neurons differentiated from T21-iPSCs. To determine GABAAR spiking activity, we will perform cell-attached patch-clamp recordings from neurons in culture and hippocampal slices before and after treatment with BZDs, while currents elicited by GABA will be recorded by whole-cell patch-clamp. In this study, we expect to provide a better understanding of molecular mechanisms underlying GABA-mediated neurotransmission and intellectual disability in DS. This study might also provide important clues toward a better clinical practice involving persons with this disorder.