Multi-influential genetic interactions alter behaviour and cognition through six main biological cascades in Down syndrome mouse models

Abstract

Down syndrome (DS) is the most common genetic form of intellectual disability caused by the presence of an additional copy of human chromosome 21 (Hsa21). To provide novel insights into genotype–phenotype correlations, we used standardized behavioural tests, magnetic resonance imaging (MRI) and hippocampal gene expression to screen several DS mouse models for the mouse chromosome 16 region homologous to Hsa21. First, we unravelled several genetic interactions between different regions of chromosome 21 and how they contribute significantly to altering the outcome of the phenotypes in brain cognition, function and structure. Then, in-depth analysis of misregulated expressed genes involved in synaptic dysfunction highlighted 6 biological cascades centred around DYRK1A, GSK3β, NPY, SNARE, RHOA and NPAS4. Finally, we provide a novel vision of the existing altered gene–gene crosstalk and molecular mechanisms targeting specific hubs in DS models that should become central to better understanding of DS and improving the development of therapies.

Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome

“…All the four groups of mice visited the same number of arms during the test, suggesting a normal locomotor activity ( S5A Fig ). On the other hand, Dp1Yey mice showed lower percentage of spontaneous alternation as compared to control mice ( Fig 5C ), confirming the phenotype already observed in previous studies [ 50 , 51 ]. This decreased performance was not restored by Dyrk1a normalization in glutamatergic neurons ( Fig 5C ).…”

“…This complex is known to mediate synaptic vesicle docking and fusion with the presynaptic membrane during neuromediator release. The SNARE complex was recently found, also with NPAS4, as a common pathway misregulated in models of DS overexpressing DYRK1A [ 50 ].…”

“…The glutamatergic system takes part in the nociceptive circuits and activation of the expression of IEGs, whose expression was found increased in Dyrk1a C/C mice, has been shown to be part of long-term events triggered in neuroadaptation to pain in those circuits [ 68 ]. Interestingly, we and our collaborators observed a decreased in the expression of some of these IEGs ( Npas4 , Arc , c-Fos and Fosb ) in the hippocampi of Tg(Dyrk1a) and of the trisomic mouse models Dp1Rhr and Ts65Dn [ 50 , 69 ]. IEGs are also believed to be crucial in the formation of long-term memory which we also found impacted in Dyrk1a C/C and trisomic mice [ 70 ].…”

“…IEGs are also believed to be crucial in the formation of long-term memory which we also found impacted in Dyrk1a C/C and trisomic mice [ 70 ]. Moreover, our meta-analysis of the transcriptomic data of hippocampi from five DS mouse models carrying Mmu16 segmental duplications and a transgenic model overexpressing Dyrk1a revealed regulatory protein networks centred around six protein hubs, among which were DYRK1A itself and NPAS4 [ 50 ]. Npas4 is a neuron-specific gene and is present in both excitatory and inhibitory neurons, activating distinct programs of late-response genes promoting inhibition onto excitatory neurons and excitation on inhibitory neurons [ 49 ].…”

“…Individuals with DS are especially affected in their explicit long-term memory abilities with a particular impairment in the visuo-perceptual processing [ 72 ]. Ts65Dn and Dp1Yey DS mouse models as well as Tg(Dyrk1a) and Dyrk1a +/- have been shown to have impaired long-term object recognition memory [ 24 , 50 , 56 , 73 ]. Novel object recognition requires a network of medial-temporal lobe regions including the hippocampus and the perirhinal-parahippocampal-entothinal and insular cortices [ 74 ].…”