Increased hippocampal epigenetic age in the Ts65Dn mouse model of Down Syndrome.

Down syndrome (DS) is a segmental progeroid genetic disorder associated with multi-systemic precocious aging phenotypes, which are particularly evident in the immune and nervous systems. Accordingly, people with DS show an increased biological age as measured by epigenetic clocks. The Ts65Dn trisomic mouse, which harbors extra-numerary copies of chromosome 21 (Hsa21)-syntenic regions, was shown to recapitulate several progeroid features of DS, but no biomarkers of age have been applied to it so far. In this pilot study, we used a mouse-specific epigenetic clock to measure the epigenetic age of hippocampi from Ts65Dn and euploid mice at 20 weeks. Ts65Dn mice showed an increased epigenetic age in comparison with controls, and the observed changes in DNA methylation partially recapitulated those observed in hippocampi from people with DS. Collectively, our results support the use of the Ts65Dn model to decipher the molecular mechanisms underlying the progeroid DS phenotypes.

Early Chronic Fluoxetine Treatment of Ts65Dn Mice Rescues Synaptic Vesicular Deficits and Prevents Aberrant Proteomic Alterations.

Down syndrome (DS) is the most common form of inherited intellectual disability caused by trisomy of chromosome 21, presenting with intellectual impairment, craniofacial abnormalities, cardiac defects, and gastrointestinal disorders. The Ts65Dn mouse model replicates many abnormalities of DS. We hypothesized that investigation of the cerebral cortex of fluoxetine-treated trisomic mice may provide proteomic signatures that identify therapeutic targets for DS. Subcellular fractionation of synaptosomes from cerebral cortices of age- and brain-area-matched samples from fluoxetine-treated vs. water-treated trisomic and euploid male mice were subjected to HPLC-tandem mass spectrometry. Analysis of the data revealed enrichment of trisomic risk genes that participate in regulation of synaptic vesicular traffic, pre-synaptic and post-synaptic development, and mitochondrial energy pathways during early brain development. Proteomic analysis of trisomic synaptic fractions revealed significant downregulation of proteins involved in synaptic vesicular traffic, including vesicular endocytosis (CLTA, CLTB, CLTC), synaptic assembly and maturation (EXOC1, EXOC3, EXOC8), anterograde axonal transport (EXOC1), neurotransmitter transport to PSD (SACM1L), endosomal-lysosomal acidification (ROGDI, DMXL2), and synaptic signaling (NRXN1, HIP1, ITSN1, YWHAG). Additionally, trisomic proteomes revealed upregulation of several trafficking proteins, involved in vesicular exocytosis (Rab5B), synapse elimination (UBE3A), scission of endocytosis (DBN1), transport of ER in dendritic spines (MYO5A), presynaptic activity-dependent bulk endocytosis (FMR1), and NMDA receptor activity (GRIN2A). Chronic fluoxetine treatment of Ts65Dn mice rescued synaptic vesicular abnormalities and prevented abnormal proteomic changes in adult Ts65Dn mice, pointing to therapeutic targets for potential treatment of DS.

Altered tongue muscle contractile properties coincide with altered swallow function in the adult Ts65Dn mouse model of down syndrome.

Purpose: Down syndrome (DS) is a developmental disability associated with difficulties in deglutition. The adult Ts65Dn mouse model of DS has been previously shown to have differences in measures of swallowing compared with euploid controls. However, the putative mechanisms of these differences in swallowing function are unclear. This study tested the hypothesis that the Ts65Dn genotype is associated with atypical measures of tongue muscle contractile properties, coinciding with atypical swallow function. Methods: Adult (5-month-old) Ts65Dn (n = 15 female, 14 male) and euploid sibling controls (n = 16 female, 14 male) were evaluated through videofluoroscopy swallow studies (VFSS) to quantify measures of swallowing performance including swallow rate and inter-swallow interval (ISI). After VFSS, retrusive tongue muscle contractile properties, including measures of muscle fatigue, were determined using bilateral hypoglossal nerve stimulation. Results: The Ts65Dn group had significantly slower swallow rates, significantly greater ISI times, significantly slower rates of tongue force development, and significantly greater levels of tongue muscle fatigue, with lower retrusive tongue forces than controls in fatigue conditions. Conclusion: Tongue muscle contractile properties are altered in adult Ts65Dn and coincide with altered swallow function.

Early chronic fasudil treatment rescues hippocampal alterations in the Ts65Dn model for down syndrome.

Down syndrome (DS) is the most common genetic disorder associated with intellectual disability. To study this syndrome, several mouse models have been developed. Among the most common is the Ts65Dn model, which mimics most of the alterations observed in DS. Ts65Dn mice, as humans with DS, show defects in the structure, density, and distribution of dendritic spines in the cerebral cortex and hippocampus. Fasudil is a potent inhibitor of the RhoA kinase pathway, which is involved in the formation and stabilization of dendritic spines. Our study analysed the effect of early chronic fasudil treatment on the alterations observed in the hippocampus of the Ts65Dn model. We observed that treating Ts65Dn mice with fasudil induced an increase in neural plasticity in the hippocampus: there was an increment in the expression of PSA-NCAM and BDNF, in the dendritic branching and spine density of granule neurons, as well as in cell proliferation and neurogenesis in the subgranular zone. Finally, the treatment reduced the unbalance between excitation and inhibition present in this model. Overall, early chronic treatment with fasudil increases cell plasticity and eliminates differences with euploid animals.

Glutamatergic synaptic deficits in the prefrontal cortex of the Ts65Dn mouse model for Down syndrome.

Down syndrome (DS), the most prevalent cause of intellectual disability, stems from a chromosomal anomaly resulting in an entire or partial extra copy of chromosome 21. This leads to intellectual disability and a range of associated symptoms. While there has been considerable research focused on the Ts65Dn mouse model of DS, particularly in the context of the hippocampus, the synaptic underpinnings of prefrontal cortex (PFC) dysfunction in DS, including deficits in working memory, remain largely uncharted territory. In a previous study featuring mBACtgDyrk1a mice, which manifest overexpression of the Dyrk1a gene, a known candidate gene linked to intellectual disability and microcephaly in DS, we documented adverse effects on spine density, alterations in the molecular composition of synapses, and the presence of synaptic plasticity deficits within the PFC. The current study aimed to enrich our understanding of the roles of different genes in DS by studying Ts65Dn mice, which overexpress several genes including Dyrk1a, to compare with our previous work on mBACtgDyrk1a mice. Through ex-vivo electrophysiological experiments, including patch-clamp and extracellular field potential recordings, we identified alterations in the intrinsic properties of PFC layer V/VI pyramidal neurons in Ts65Dn male mice. Additionally, we observed changes in the synaptic plasticity range. Notably, long-term depression was absent in Ts65Dn mice, while synaptic or pharmacological long-term potentiation remained fully expressed in these mice. These findings provide valuable insights into the intricate synaptic mechanisms contributing to PFC dysfunction in DS, shedding light on potential therapeutic avenues for addressing the neurocognitive symptoms associated with this condition.

Ultrasonic vocalization phenotypes in the Ts65Dn and Dp(16)1Yey mouse models of Down syndrome.

Down syndrome (DS) is a developmental disorder associated with a high incidence of challenges in vocal communication. DS can involve medical co-morbidities and structural social factors that may impact communication outcomes, which can present difficulties for the study of vocal communication challenges. Mouse models of DS may be used to study vocal communication differences associated with this syndrome and allow for greater control and consistency of environmental factors. Prior work has demonstrated differences in ultrasonic vocalization (USV) of the Ts65Dn mouse model of DS at a young adult age, however it is not known how USV characteristics are manifested at mature ages. Given that the aging process and age-related co-morbidities may also impact communication in DS, addressing this gap in knowledge may be of value for efforts to understand communication difficulties in DS across the lifespan. The current study hypothesized that the Ts65Dn and Dp(16)1Yey mouse models of DS would demonstrate differences in multiple measures of USV communication at a mature adult age of 5 months. METHODS: Ts65Dn mice (n = 16) and euploid controls (n = 19), as well as Dp(16)1Yey mice (n = 20) and wild-type controls (n = 22), were evaluated at 5 months of age for USV production using a mating paradigm. Video footage of USV sessions were analyzed to quantify social behaviors of male mice during USV testing sessions. USV recordings were analyzed using Deepsqueak software to identify 10 vocalization types, which were quantified for 11 acoustic measures. RESULTS: Ts65Dn, but not Dp(16)1Yey, showed significantly lower proportions of USVs classified as Step Up, Short, and Frequency Steps, and significantly higher proportions of USVs classified as Inverted U, than euploid controls. Both Ts65Dn and Dp(16)1Yey groups had significantly greater values for power and tonality for USVs than respective control groups. While Ts65Dn showed lower frequencies than controls, Dp(16)1Yey showed higher frequencies than controls. Finally, Ts65Dn showed reductions in a measure of complexity for some call types. No significant differences between genotype groups were identified in analysis of behaviors during testing sessions. CONCLUSION: While both Ts65Dn and Dp(16)1Yey show significant differences in USV measures at 5 months of age, of the two models, Ts65Dn shows a relatively greater numbers of differences. Characterization of communication phenotypes in mouse models of DS may be helpful in laying the foundation for future translational advances in the area of communication difficulties associated with DS.

Retromer Stabilization Improves Cognitive Function and Synaptic Plasticity in a Mouse Model of Down Syndrome.

BACKGROUND: Retromer complex proteins are decreased in postmortem brain tissues from Down syndrome subjects and inversely correlate with the Alzheimer's disease-like neuropathology. However, whether targeting in vivo the retromer system affects cognitive deficits and synaptic function in Down syndrome remains unknown. OBJECTIVE: The aim of the current study was to examine the effects of pharmacological retromer stabilization on cognitive and synaptic functions in a mouse model of Down syndrome. METHODS: Ts65dn mice were administered the pharmacological chaperone, TPT-172, or vehicle from 4 to 9 months of age and then assessed for changes in cognitive function. To assess the effects of TPT-172 on synaptic plasticity, hippocampal slices from Ts65dn mice were incubated in TPT-172 and used for field potential recordings. RESULTS: Chronic TPT-172 treatment improved performance in cognitive function tests, its incubation with hippocampal slices ameliorated synaptic function response. CONCLUSION: Pharmacological stabilization of the retromer complex improves synaptic plasticity and memory in a mouse model of Down syndrome. These results support the therapeutic potential of pharmacological retromer stabilization for individual with Down syndrome.

Physical Training Chronically Stimulates the Motor Neuron Cell Nucleus in the Ts65Dn Mouse, a Model of Down Syndrome.

Down syndrome (DS) is a genetically-based disease based on the trisomy of chromosome 21 (Hsa21). DS is characterized by intellectual disability in association with several pathological traits among which early aging and altered motor coordination are prominent. Physical training or passive exercise were found to be useful in counteracting motor impairment in DS subjects. In this study we used the Ts65Dn mouse, a widely accepted animal model of DS, to investigate the ultrastructural architecture of the medullary motor neuron cell nucleus taken as marker of the cell functional state. Using transmission electron microscopy, ultrastructural morphometry, and immunocytochemistry we carried out a detailed investigation of possible trisomy-related alteration(s) of nuclear constituents, which are known to vary their amount and distribution as a function of nuclear activity, as well as the effect of adapted physical training upon them. Results demonstrated that trisomy per se affects nuclear constituents to a limited extent; however, adapted physical training is able to chronically stimulate pre-mRNA transcription and processing activity in motor neuron nuclei of trisomic mice, although to a lesser extent than in their euploid mates. These findings are a step towards understanding the mechanisms underlying the positive effect of physical activity in DS.

Emergence of Treadmill Running Ability and Quantitative Assessment of Gait Dynamics in Young Ts65Dn Mice: A Mouse Model for Down Syndrome.

Down syndrome (DS), which results from the complete or partial trisomy of chromosome 21 (trisomy-21), is the most common genetically defined cause of intellectual disability. Trisomy-21 also produces, or is associated with, many neurodevelopmental phenotypes and neurological comorbidities, including delays and deficits in fine and gross motor development. The Ts65Dn mouse is the most studied animal model for DS and displays the largest known subset of DS-like phenotypes. To date, however, only a small number of developmental phenotypes have been quantitatively defined in these animals. Here, we used a commercially available high-speed, video-based system to record and analyze the gait of Ts65Dn and euploid control mice. Longitudinal treadmill recordings were performed from p17 to p35. One of the main findings was the detection of genotype- and sex-dependent developmental delays in the emergence of consistent, progressive-intensity gait in Ts65Dn mice when compared to control mice. Gait dynamic analysis showed wider normalized front and hind stances in Ts65Dn mice compared to control mice, which may reflect deficits in dynamic postural balance. Ts65Dn mice also displayed statistically significant differences in the variability in several normalized gait measures, which were indicative of deficits in precise motor control in generating gait.

A Multimodal Imaging-Supported Down Syndrome Mouse Model of RSV Infection.

Individuals with Down syndrome (DS) are more prone to develop severe respiratory tract infections. Although a RSV infection has a high clinical impact and severe outcome in individuals with DS, no vaccine nor effective therapeutics are available. Any research into infection pathophysiology or prophylactic and therapeutic antiviral strategies in the specific context of DS would greatly benefit this patient population, but currently such relevant animal models are lacking. This study aimed to develop and characterize the first mouse model of RSV infection in a DS-specific context. Ts65Dn mice and wild type littermates were inoculated with a bioluminescence imaging-enabled recombinant human RSV to longitudinally track viral replication in host cells throughout infection progression. This resulted in an active infection in the upper airways and lungs with similar viral load in Ts65Dn mice and euploid mice. Flow cytometric analysis of leukocytes in lungs and spleen demonstrated immune alterations with lower CD8+ T cells and B-cells in Ts65Dn mice. Overall, our study presents a novel DS-specific mouse model of hRSV infection and shows that potential in using the Ts65Dn preclinical model to study immune-specific responses of RSV in the context of DS and supports the need for models representing the pathological development.

The Impact of Mmu17 Non-Hsa21 Orthologous Genes in the Ts65Dn Mouse Model of Down Syndrome: The Gold Standard Refuted.

BACKGROUND: Despite successful preclinical treatment studies to improve neurocognition in the Ts65Dn mouse model of Down syndrome, translation to humans has failed. This raises questions about the appropriateness of the Ts65Dn mouse as the gold standard. We used the novel Ts66Yah mouse that carries an extra chromosome and the identical segmental Mmu16 trisomy as Ts65Dn without the Mmu17 non-Hsa21 orthologous region. METHODS: Forebrains from embryonic day 18.5 Ts66Yah and Ts65Dn mice, along with euploid littermate controls, were used for gene expression and pathway analyses. Behavioral experiments were performed in neonatal and adult mice. Because male Ts66Yah mice are fertile, parent-of-origin transmission of the extra chromosome was studied. RESULTS: Forty-five protein-coding genes mapped to the Ts65Dn Mmu17 non-Hsa21 orthologous region; 71%-82% are expressed during forebrain development. Several of these genes are uniquely overexpressed in Ts65Dn embryonic forebrain, producing major differences in dysregulated genes and pathways. Despite these differences, the primary Mmu16 trisomic effects were highly conserved in both models, resulting in commonly dysregulated disomic genes and pathways. Delays in motor development, communication, and olfactory spatial memory were present in Ts66Yah but more pronounced in Ts65Dn neonates. Adult Ts66Yah mice showed milder working memory deficits and sex-specific effects in exploratory behavior and spatial hippocampal memory, while long-term memory was preserved. CONCLUSIONS: Our findings suggest that triplication of the non-Hsa21 orthologous Mmu17 genes significantly contributes to the phenotype of the Ts65Dn mouse and may explain why preclinical trials that used this model have unsuccessfully translated to human therapies.

Oxidative-Stress-Associated Proteostasis Disturbances and Increased DNA Damage in the Hippocampal Granule Cells of the Ts65Dn Model of Down Syndrome.

Oxidative stress (OS) is one of the neuropathological mechanisms responsible for the deficits in cognition and neuronal function in Down syndrome (DS). The Ts65Dn (TS) mouse replicates multiple DS phenotypes including hippocampal-dependent learning and memory deficits and similar brain oxidative status. To better understand the hippocampal oxidative profile in the adult TS mouse, we analyzed cellular OS-associated alterations in hippocampal granule cells (GCs), a neuronal population that plays an important role in memory formation and that is particularly affected in DS. For this purpose, we used biochemical, molecular, immunohistochemical, and electron microscopy techniques. Our results indicate that TS GCs show important OS-associated alterations in the systems essential for neuronal homeostasis: DNA damage response and proteostasis, particularly of the proteasome and lysosomal system. Specifically, TS GCs showed: (i) increased DNA damage, (ii) reorganization of nuclear proteolytic factories accompanied by a decline in proteasome activity and cytoplasmic aggregation of ubiquitinated proteins, (iii) formation of lysosomal-related structures containing lipid droplets of cytotoxic peroxidation products, and (iv) mitochondrial ultrastructural defects. These alterations could be implicated in enhanced cellular senescence, accelerated aging and neurodegeneration, and the early development of Alzheimer's disease neuropathology present in TS mice and the DS population.

Postnatal environmental enrichment enhances memory through distinct neural mechanisms in healthy and trisomic female mice.

Stimulating lifestyles have powerful effects on cognitive abilities, especially when they are experienced early in life. Cognitive therapies are widely used to improve cognitive impairment due to intellectual disability, aging, and neurodegeneration, however the underlying neural mechanisms are poorly understood. We investigated the neural correlates of memory amelioration produced by postnatal environmental enrichment (EE) in diploid mice and the Ts65Dn mouse model of Down syndrome (trisomy 21). We recorded neural activities in brain structures key for memory processing, the hippocampus and the prefrontal cortex, during rest, sleep and memory performance in mice reared in non-enriched or enriched environments. Enriched wild-type animals exhibited enhanced neural synchrony in the hippocampus across different brain states (increased gamma oscillations, theta-gamma coupling, sleep ripples). Trisomic females showed increased theta and gamma rhythms in the hippocampus and prefrontal cortex across different brain states along with enlarged ripples and disrupted circuit gamma signals that were associated with memory deficits. These pathological activities were attenuated in their trisomic EE-reared peers. Our results suggest distinct neural mechanisms for the generation and rescue of healthy and pathological brain synchrony, respectively, by EE and put forward hippocampal-prefrontal hypersynchrony and miscommunication as major targets underlying the beneficial effects of EE in intellectual disability.

Cholinergic Senescence in the Ts65Dn Mouse Model for Down Syndrome.

Down syndrome (DS) induces a variable phenotype including intellectual disabilities and early development of Alzheimer's disease (AD). Moreover, individuals with DS display accelerated aging that affects diverse organs, among them the brain. The Ts65Dn mouse is the most widely used model to study DS. Progressive loss of cholinergic neurons is one of the hallmarks of AD present in DS and in the Ts65Dn model. In this study, we quantify the number of cholinergic neurons in control and Ts65Dn mice, observing a general reduction in their number with age but in particular, a greater loss in old Ts65Dn mice. Increased expression of the m1 muscarinic receptor in the hippocampus counteracts this loss. Cholinergic neurons in the Ts65Dn mice display overexpression of the early expression gene c-fos and an increase in the expression of ß-galactosidase, a marker of senescence. A possible mechanism for senescence induction could be phosphorylation of the transcription factor FOXO1 and its retention in the cytoplasm, which we are able to confirm in the Ts65Dn model. In our study, using Ts65Dn mice, we observe increased cholinergic activity, which induces a process of early senescence that culminates in the loss of these neurons.

Temporal and brain region-specific elevations of soluble Amyloid-ß40-42 in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease.

Down syndrome (DS) is a leading cause of intellectual disability that also results in hallmark Alzheimer's disease (AD) pathologies such as amyloid beta (Aß) plaques and hyperphosphorylated tau. The Ts65Dn mouse model is commonly used to study DS, as trisomic Ts65Dn mice carry 2/3 of the triplicated gene homologues as occur in human DS. The Ts65Dn strain also allows investigation of mechanisms common to DS and AD pathology, with many of these triplicated genes implicated in AD; for example, trisomic Ts65Dn mice overproduce amyloid precursor protein (APP), which is then processed into soluble Aß40-42 fragments. Notably, Ts65Dn mice show alterations to the basal forebrain, which parallels the loss of function in this region observed in DS and AD patients early on in disease progression. However, a complete picture of soluble Aß40-42 accumulation in a region-, age-, and sex-specific manner has not yet been characterized in the Ts65Dn model. Here, we show that trisomic mice accumulate soluble Aß40-42 in the basal forebrain, frontal cortex, hippocampus, and cerebellum in an age-specific manner, with elevation in the frontal cortex and hippocampus as early as 4 months of age. Furthermore, we detected sex differences in accumulation of Aß40-42 within the basal forebrain, with females having significantly higher Aß40-42 at 7-8 months of age. Lastly, we show that APP expression in the basal forebrain and hippocampus inversely correlates with Aß40-42  levels. This spatial and temporal characterization of soluble Aß40-42 in the Ts65Dn model allows for further exploration of the role soluble Aß plays in the progression of other AD-like pathologies in these key brain regions.

Differential expression of the neuronal CB1 cannabinoid receptor in the hippocampus of male Ts65Dn Down syndrome mouse model.

Down syndrome (DS) or Trisomy 21 is the most common genetic cause of mental retardation with severe learning and memory deficits. DS is due to the complete or partial triplication of human chromosome 21 (HSA21) triggering gene overexpression and protein synthesis alterations responsible for a plethora of mental and physical phenotypes. Among the diverse brain target systems that affect hippocampal-dependent learning and memory deficit impairments in DS, the upregulation of the endocannabinoid system (ECS), and notably the overexpression of the cannabinoid type-1 receptor (CB1), seems to play a major role. Combining various protein and gene expression targeted approaches using western blot, qRT-PCR and FISH techniques, we investigated the expression pattern of ECS components in the hippocampus (HPC) of male Ts65Dn mice. Among all the molecules that constitute the ECS, we found that the expression of the CB1 is altered in the HPC of Ts65Dn mice. CB1 distribution is differentially segregated between the dorsal and ventral part of the HPC and within the different cell populations that compose the HPC. CB1 expression is upregulated in GABAergic neurons of Ts65Dn mice whereas it is downregulated in glutamatergic neurons. These results highlight a complex regulation of the CB1 encoding gene (Cnr1) in Ts65Dn mice that could open new therapeutic solutions for this syndrome.

Evidence of Energy Metabolism Alterations in Cultured Neonatal Astrocytes Derived from the Ts65Dn Mouse Model of Down Syndrome.

For many decades, neurons have been the central focus of studies on the mechanisms underlying the neurodevelopmental and neurodegenerative aspects of Down syndrome (DS). Astrocytes, which were once thought to have only a passive role, are now recognized as active participants of a variety of essential physiological processes in the brain. Alterations in their physiological function have, thus, been increasingly acknowledged as likely initiators of or contributors to the pathogenesis of many nervous system disorders and diseases. In this study, we carried out a series of real-time measurements of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in hippocampal astrocytes derived from neonatal Ts65Dn and euploid control mice using a Seahorse XFp Flux Analyzer. Our results revealed a significant basal OCR increase in neonatal Ts65Dn astrocytes compared with those from control mice, indicating increased oxidative phosphorylation. ECAR did not differ between the groups. Given the importance of astrocytes in brain metabolic function and the linkage between astrocytic and neuronal energy metabolism, these data provide evidence against a pure "neurocentric" vision of DS pathophysiology and support further investigations on the potential contribution of disturbances in astrocytic energy metabolism to cognitive deficits and neurodegeneration associated with DS.

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

Down syndrome (DS) in humans is caused by trisomy of chromosome 21 and is marked by prominent difficulties in learning and memory. Decades of research have demonstrated that the hippocampus is a key structure in learning and memory, and recent work with mouse models of DS has suggested differences in hippocampal activity that may be the substrate of these differences. One of the primary functional differences in DS is thought to be an excess of GABAergic innervation from medial septum to the hippocampus. In these experiments, we probe in detail the activity of region CA1 of the hippocampus using in vivo electrophysiology in male Ts65Dn mice compared with their male nontrisomic 2N littermates. We find the spatial properties of place cells in CA1 are normal in Ts65Dn animals. However, we find that the phasic relationship of both CA1 place cells and gamma rhythms to theta rhythm in the hippocampus is profoundly altered in these mice. Since the phasic organization of place cell activity and gamma oscillations on the theta wave are thought to play a critical role in hippocampal function, the changes we observe agree with recent findings that organization of the hippocampal network is potentially of more relevance to its function than the spatial properties of place cells.SIGNIFICANCE STATEMENT Recent evidence has disrupted the view that spatial deficits are associated with place cell abnormalities. In these experiments, we record hippocampal place cells and local field potential from the Ts65Dn mouse model of Down syndrome, and find phenomenologically normal place cells, but profound changes in the association of place cells and gamma rhythms with theta rhythm, suggesting that the overall network state is critically important for hippocampal function. These findings also agree with evidence suggesting that excess inhibitory control is the cause of hippocampal dysfunction in Down syndrome. The findings also confirm new avenues for pharmacological treatment of Down syndrome.

Early Appearance of Dendritic Alterations in Neocortical Pyramidal Neurons of the Ts65Dn Model of Down Syndrome.

Down syndrome (DS), which is due to triplication of chromosome 21, is constantly associated with intellectual disability (ID). ID can be ascribed to both neurogenesis impairment and dendritic pathology. These defects are replicated in the Ts65Dn mouse, a widely used model of DS. While neurogenesis impairment in DS is a fetal event, dendritic pathology occurs after the first postnatal months. Neurogenesis alterations across the life span have been extensively studied in the Ts65Dn mouse. In contrast, there is scarce information regarding dendritic alterations at early life stages in this and other models, although there is evidence for dendritic alterations in adult mouse models. Thus, the goal of the current study was to establish whether dendritic alterations are already present in the neonatal period in Ts65Dn mice. In Golgi-stained brains, we quantified the dendritic arbors of layer II/III pyramidal neurons in the frontal cortex of Ts65Dn mice aged 2 (P2) and 8 (P8) days and their euploid littermates. In P2 Ts65Dn mice, we found a moderate hypotrophy of the apical and collateral dendrites but a patent hypotrophy of the basal dendrites. In P8 Ts65Dn mice, the distalmost apical branches were missing or reduced in number, but there were no alterations in the collateral and basal dendrites. No genotype effects were detected on either somatic or dendritic spine density. This study shows dendritic branching defects that mainly involve the basal domain in P2 Ts65Dn mice and the apical but not the other domains in P8 Ts65Dn mice. This suggests that dendritic defects may be related to dendritic compartment and age. The lack of a severe dendritic pathology in Ts65Dn pups is reminiscent of the delayed appearance of patent dendritic alterations in newborns with DS. This similarly highlights the usefulness of the Ts65Dn model for the study of the mechanisms underlying dendritic alterations in DS and the design of possible therapeutic interventions.