Down syndrome (DS) is due to increased copy number of human chromosome 21. The contribution of different genetic regions has been tested using mouse models. As shown previously, the Abcg1-U2af1 genetic region contributes to cognitive defects in working and short-term recognition memory in Down syndrome mouse models. Here we analyzed the impact of monosomy of the same genetic interval, using a new mouse model, named Ms2Yah. We used several cognitive paradigms and did not detect defects in the object recognition or the Morris water maze tests. However, surprisingly, Ms2Yah mice displayed increased associative memory in a pure contextual fear-conditioning test and decreased social novelty interaction along with a larger long-term potentiation recorded in the CA1 area following stimulation of Schaffer collaterals. Whole-genome expression studies carried out on hippocampus showed that the transcription of only a small number of genes is affected, mainly from the genetic interval (Cbs, Rsph1, Wdr4), with a few additional ones, including the postsynaptic Gabrr2, Gabbr1, Grid2p, Park2, and Dlg1 and the components of the Ubiquitin-mediated proteolysis (Anapc1, Rnf7, Huwe1, Park2). The Abcg1-U2af1 region is undeniably encompassing dosage-sensitive genes or elements whose change in copy number directly affects learning and memory, synaptic function, and autistic related behavior.

Mental retardation in Down syndrome (DS), the most frequent trisomy in humans, varies from moderate to severe. Several studies both in human and based on mouse models identified some regions of human chromosome 21 (Hsa21) as linked to cognitive deficits. However, other intervals such as the telomeric region of Hsa21 may contribute to the DS phenotype but their role has not yet been investigated in detail. Here we show that the trisomy of the 12 genes, found in the 0.59 Mb (Abcg1-U2af1) Hsa21 sub-telomeric region, in mice (Ts1Yah) produced defects in novel object recognition, open-field and Y-maze tests, similar to other DS models, but induces an improvement of the hippocampal-dependent spatial memory in the Morris water maze along with enhanced and longer lasting long-term potentiation in vivo in the hippocampus. Overall, we demonstrate the contribution of the Abcg1-U2af1 genetic region to cognitive defect in working and short-term recognition memory in DS models. Increase in copy number of the Abcg1-U2af1 interval leads to an unexpected gain of cognitive function in spatial learning. Expression analysis pinpoints several genes, such as Ndufv3, Wdr4, Pknox1 and Cbs, as candidates whose overexpression in the hippocampus might facilitate learning and memory in Ts1Yah mice. Our work unravels the complexity of combinatorial genetic code modulating different aspect of mental retardation in DS patients. It establishes definitely the contribution of the Abcg1-U2af1 orthologous region to the DS etiology and suggests new modulatory pathways for learning and memory.

In this study, we investigated the impact of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) overexpression, a gene associated with Down syndrome, on hippocampal neuronal deficits in mice. Our findings revealed that mice overexpressing Dyrk1A (TgDyrk1A; TG) exhibited impaired hippocampal recognition memory, disrupted excitation-inhibition balance, and deficits in long-term potentiation (LTP). Specifically, we observed layer-specific deficits in dendritic arborization of TG CA1 pyramidal neurons in the stratum radiatum. Through computational modeling, we determined that these alterations resulted in reduced storage capacity and compromised integration of inputs, with decreased high γ oscillations. Contrary to prevailing assumptions, our model suggests that deficits in neuronal architecture, rather than over-inhibition, primarily contribute to the reduced network. We explored the potential of environmental enrichment (EE) as a therapeutic intervention and found that it normalized the excitation-inhibition balance, restored LTP, and improved short-term recognition memory. Interestingly, we observed transient significant dendritic remodeling, leading to recovered high γ. However, these effects were not sustained after EE discontinuation. Based on our findings, we conclude that Dyrk1A overexpression-induced layer-specific neuromorphological disturbances impair the encoding of place and temporal context. These findings contribute to our understanding of the underlying mechanisms of Dyrk1A-related hippocampal deficits and highlight the challenges associated with long-term therapeutic interventions for cognitive impairments.

Addiction involves long-lasting maladaptive changes including development of disruptive drug-stimuli associations. Nicotine-induced neuroplasticity underlies the development of tobacco addiction but also, in regions such as the hippocampus, the ability of this drug to enhance cognitive capabilities. Here, we propose that the genetic locus of susceptibility to nicotine addiction, the CHRNA5/A3/B4 gene cluster, encoding the α5, α3 and β4 subunits of the nicotinic acetylcholine receptors (nAChRs), may influence nicotine-induced neuroadaptations. We have used transgenic mice overexpressing the human cluster (TgCHRNA5/A3/B4) to investigate hippocampal structure and function in genetically susceptible individuals. TgCHRNA5/A3/B4 mice presented a marked reduction in the dendrite complexity of CA1 hippocampal pyramidal neurons along with an increased dendritic spine density. In addition, TgCHRNA5/A3/B4 exhibited increased VGLUT1/VGAT ratio in the CA1 region, suggesting an excitatory/inhibitory imbalance. These hippocampal alterations were accompanied by a significant impairment in short-term novelty recognition memory. Interestingly, chronic infusion of nicotine (3.25 mg/kg/d for 7 d) was able to rescue the reduced dendritic complexity, the excitatory/inhibitory imbalance and the cognitive impairment in TgCHRNA5/A3/B4. Our results suggest that chronic nicotine treatment may represent a compensatory strategy in individuals with altered expression of the CHRNA5/A3/B4 region.

Abnormal dendritic arbors, dendritic spine "dysgenesis" and excitation inhibition imbalance are main traits assumed to underlie impaired cognition and behavioral adaptation in intellectual disability. However, how these modifications actually contribute to functional properties of neuronal networks, such as signal integration or storage capacity is unknown. Here, we used a mouse model overexpressing Dyrk1A (Dual-specificity tyrosine [Y]-regulated kinase), one of the most relevant Down syndrome (DS) candidate genes, to gather quantitative data regarding hippocampal neuronal deficits produced by the overexpression of Dyrk1A in mice (TgDyrk1A; TG). TG mice showed impaired hippocampal recognition memory, altered excitation-inhibition balance and deficits in hippocampal CA1 LTP. We also detected for the first time that deficits in dendritic arborization in TG CA1 pyramidal neurons are layer-specific, with a reduction in the width of the stratum radiatum , the postsynaptic target site of CA3 excitatory neurons, but not in the stratum lacunosum-moleculare , which receives temporo-ammonic projections. To interrogate about the functional impact of layer-specific TG dendritic deficits we developed tailored computational multicompartmental models. Computational modelling revealed that neuronal microarchitecture alterations in TG mice lead to deficits in storage capacity, altered the integration of inputs from entorhinal cortex and hippocampal CA3 region onto CA1 pyramidal cells, important for coding place and temporal context and on connectivity and activity dynamics, with impaired the ability to reach high γ oscillations. Contrary to what is assumed in the field, the reduced network activity in TG is mainly contributed by the deficits in neuronal architecture and to a lesser extent by over-inhibition. Finally, given that therapies aimed at improving cognition have also been tested for their capability to recover dendritic spine deficits and excitation-inhibition imbalance, we also tested the short- and long-term changes produced by exposure to environmental enrichment (EE). Exposure to EE normalized the excitation inhibition imbalance and LTP, and had beneficial effects on short-term recognition memory. Importantly, it produced massive but transient dendritic remodeling of hippocampal CA1, that led to recovery of high γ oscillations, the main readout of synchronization of CA1 neurons, in our simulations. However, those effects where not stable and were lost after EE discontinuation. We conclude that layer-specific neuromorphological disturbances produced by Dyrk1A overexpression impair coding place and temporal context. Our results also suggest that treatments targeting structural plasticity, such as EE, even though hold promise towards improved treatment of intellectual disabilities, only produce temporary recovery, due to transient dendritic remodeling.