Signalling pathways contributing to learning and memory deficits in the Ts65Dn mouse model of Down syndrome

Abstract

Down syndrome (DS) is a genetic trisomic disorder that produces life-long changes in physiology and cognition. Many of the changes in learning and memory seen in DS are reminiscent of disorders involving the hippocampal/entorhinal circuit. Mouse models of DS typically involve trisomy of murine chromosome 16 is homologous for many of the genes triplicated in human trisomy 21, and provide us with good models of changes in, and potential pharmacotherapy for, human DS. Recent careful dissection of the Ts65Dn mouse model of DS has revealed differences in key signalling pathways from the basal forebrain to the hippocampus and associated rhinal cortices, as well as changes in the microstructure of the hippocampus itself. In vivo behavioural and electrophysiological studies have shown that Ts65Dn animals have difficulties in spatial memory that mirror hippocampal deficits, and have changes in hippocampal electrophysiological phenomenology that may explain these differences, and align with expectations generated from in vitro exploration of this model. Finally, given the existing data, we will examine the possibility for pharmacotherapy for DS, and outline the work that remains to be done to fully understand this system.

GnRH replacement rescues cognition in Down syndrome

“…In terms of neuronal activity, cognitive deficits in Ts65Dn mice could result from alterations of synaptic plasticity and neurotransmission (73). Aberrant g-aminobutyric acid (GABA)-mediated (GABAergic) signaling has been previously observed in Ts65Dn mice (74), as has altered long-term potentiation associated with increased hippocampal GABA release (75) and GABAergic inhibition (76,77). Synaptic transmission in the hippocampus of our Ts65Dn mice was partly normalized by miR-200b overexpression in the septal POA, with which it is reciprocally connected (78) and which is a source of hippocampal GABAergic neurons during embryogenesis (79).…”

Hyper-Rigid Phasic Organization of Hippocampal Activity But Normal Spatial Properties of CA1 Place Cells in the Ts65Dn Mouse Model of Down Syndrome

“…Individuals with DS exhibit deficits in learning and memory (Simon et al, 2009;Lott and Dierssen, 2010). The Ts65Dn mouse model provides replication of changes seen in human DS (Freeburn and Munn, 2021).…”

Overproduction of hydrogen sulfide, generated by cystathionine β-synthase, disrupts brain wave patterns and contributes to neurobehavioral dysfunction in a rat model of down syndrome

“…Measurements of ex vivo H 2 S generation performed in the current study suggest that the hippocampus may be one of the most significant sources (and possible target) H 2 S overproduction. Indeed, the hippocampus is one of the brain regions with the highest relative percentage of astrocytes [ 51 ] and a significant brain region involved in learning and memory deficits in DS [ [51] , [52] , [53] , [54] ]. Other neuroanatomical systems including prefrontal cortex are also relevant to cognitive functions and could influence attention, memory and cognitive flexibility.…”

“…Artifact-free LFPs were used for all further analyses. Power spectra were calculated as described [ 29 , 54 ] for each epoch by fast Fourier transform. Gamma (γ) power was calculated by taking the mean value of the power spectrum between 30 and 80 Hz.…”