24 July 2021
Alterations of brain circuits in Down syndrome murine models / Gotti S.; Caricati E.; Panzica G.. - In: JOURNAL OF CHEMICAL NEUROANATOMY. - ISSN 0891-0618. - STAMPA. - 42(2011), pp. 317-326.
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Alterations of brain circuits in Down syndrome murine models
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DOI:10.1016/j.jchemneu.2011.09.002
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Gotti et al. - Prepared for J. Chemical Neuroanatomy 04/09/2011
Alterations of brain circuits in Down syndrome murine models
Stefano Gotti * 1,2, Egidio Caricati1,2, GianCarlo Panzica1,2
1 - Laboratory of Neuroendocrinology, Neuroscience Institute of Torino (NIT), National Institute of Neuroscience (INN, Torino), Dept. Anatomy, Pharmacology and Forensic Medicine, University of Torino, corso M. D’Azeglio 52, 10126 – Torino, Italy
2 - Neuroscience Institute of Cavalieri-Ottolenghi foundation (NICO), Torino, Italy
* Corresponding author: Stefano Gotti Laboratory of Neuroendocrinology,
Neuroscience Institute Cavalieri-Ottolenghi (NICO), Regione Gonzole, 10 – 10043 Orbassano (TO), Italy Tel.: +39 011 6707054; fax: +39 011 6705931. e-mail: stefano.gotti@unito.it
Abstract
Trisomy 21, also referred to Down syndrome (DS), is the most common genetic cause of mental retardation, affecting 1 each 800-1000 newborn children all over the world. DS is a complex disease, determined by an extra copy of human chromosome 21 that causes an imbalanced gene dose effect. The syntenies that exist between mouse chromosomes 10, 16, and 17 and human chromosome 21 offer the opportunity for a genotype–phenotype correlation and several mouse models of DS have been developed to improve our knowledge about cognitive disabilities and brain alterations.
We present here the different murine models available up to now and we discuss the neural alterations that have been described in these strains. The largest amount of studies involved the so called Ts65Dn mouse showing early alterations of nitrergic, noradrenergic and cholinergic systems at the level of the basal forebrain. Neurogenesis and spine formations are decreased in the hippocampus, as well as the whole size of the cerebellum and the number of granule cells.
Keywords
1. Introduction
In 1959, Lejeune and coworkers discovered the association between the syndrome described in 1867 by John Langdon Down and the triplication of the human chromosome 21 (HSA21) (Lejeune et al., 1959). Today, the Down Syndrome (DS) is considered the most common genetic cause of mental retardation (Hassold and Jacobs, 1984) affecting 1 each 800-1000 newborn children all over the world (Roizen and Patterson, 2003).
DS is determined by a chromosomal aberration that involves the total or partial trisomy of HSA21, resulting from meiotic non-disjunction of the chromosome 21 pair (95%). About 4% of persons with DS have 46 chromosomes, one of which is carrying a Robertsonian translocation between chromosome 21q and the long arm of one of the other acrocentric chromosomes (usually chromosome 14 or 22). About 1% of persons with DS have a mosaicism, with cell populations showing either a normal or a trisomic 21 karyotype; in this case, the phenotype may be milder than that of typical 21 trisomy (Hook, 1981; Patterson, 1987; Nadal et al., 1996; Galdzicki et al., 2001).
A precise gene catalogue for HSA21 has not yet been determined, in fact its sequencing (Hattori et al., 2000) showed 225 genes and 59 pseudo genes, but the prediction based on estimation from the sequencing is of 364 genes (Gardiner et al., 2003; Gardiner and Costa, 2006). Most of the functions of these genes are still unknown. An additional, unexpected finding is that the actual fraction of chromosome 21 transcribed into RNA might be one order of magnitude higher than the fraction occupied by gene coding sequences (Kapranov et al., 2002).
Different hypotheses have been presented to account for the relationships between trisomy of HSA21 and the occurrence of DS phenotypes.
“Gene dosage effect hypothesis”: According to this hypotesis, DS phenotype is a direct consequence of the cumulative effects of the dosage imbalance of genes located on the triplicate chromosome (Epstein, 1986, 1990; Korenberg et al., 1990). A subset of genes on HSA21 is therefore directly responsible for the pathological traits associated with trisomy 21.
“Down Syndrome Critical Region (DSCR) hypothesis”: DS associated with partial 21 trisomy is very rarely observed (no more than 1% of living trisomic persons), but these persons are of particular interest because they allowed the
identification of a restricted region of HSA21, called Down syndrome critical region (DSCR), located on the distal third of the long arm of the chromosome (region 21q22). The DSCR hypothesis states that genes in this region, when present in three copies, are responsible for the DS phenotypes and may cause the disease (Hardy et al., 1989). DSCR was in fact associated with the expression of many features of DS like the dysmorphic phenotypes and the mental retardation (Delabar et al., 1993; Korenberg et al., 1994); this hypothesis is in agreement with the gene dosage effect hypothesis.
Recent studies performed in mice models of DS (see below) have shown that three copies of DSCR genes alone are not sufficient to generate the craniofacial dysmorphic phenotypes (Olson et al., 2004). On the contrary, other studies show that DSCR genes are necessary but not sufficient to determine the impairment of the hippocampal function (Olson et al., 2007).
“Amplified developmental instability hypothesis”: the dosage imbalance of
hundreds of genes on HSA21 determines a non-specific perturbation of genomic regulation and expression; in this case, it is not the presence of three copies of a particular gene but rather the presence of a threshold number of genes (no matter the genes) that leads to DS phenotypes (Patterson and Costa 2005).
In summary, these hypotheses led to the conclusion that DS depends on a genetic unbalance determined either by the expression of trisomic genes (Mao et al., 2005) or by a destabilization in the expression of many disomic genes induced by the increased expression of trisomic genes (Saran et al., 2003). This last hypothesis is supported for example by the reduction of the level of the alpha fetoprotein (Newby et al., 1997) or by the increase in the human chorionic gonadotrophin levels (Macri et al., 1993) in trisomy 21, while the corresponding genes are located not on HSA21, but on 4 and 19, respectively.
2. Phenotype of Down Syndrome
Adult individuals with DS present a wide range of phenotypic and physiological abnormalities, including craniofacial anomalies, and diminished male reproductive
capacities (Bovicelli et al., 1982).
More interesting for the aims of this paper, the most salient feature of DS is mental retardation. In fact, DS is characterized by abnormalities in learning, memory, and language that lead to mild-profound impairment of intellectual functions. Individuals with DS have more behavioral and psychiatric problems than other persons: 17% of individuals with DS less than 20 year old have a psychiatric disorder, most frequently a disruptive behavior disorder such as attention deficit hyperactivity disorder (6%), conduct/oppositional disorder (5%), or aggressive behavior (6%); 25% of adults with DS have a psychiatric disorder, most frequently a major depressive disorder (6%) or aggressive behavior (6%) (Roizen and Patterson, 2003).
Several differences of DS brains compared to non-DS ones have been described, with both post-mortem and magnetic resonance analyses. In particular, several macroscopical abnormalities were found: i.e., small cerebellum, reduced frontal, temporal, and occipital lobes, reduced number and depth of the cerebral sulci, reduced cerebral grey and white matter, reduced hippocampal volume, and an age-related decrease of corpus callosum (for a complete references see Roubertoux and Kerdhule, 2006; Teipel and Hampel, 2006).
Several neuronal abnormalities, including alteration of cortical lamination, reduced dendritic branching, and diminished number of synapses, have been also described (see for references Roizen and Patterson, 2003). Neuronal alterations are accompanied with changes of glial elements: astrocyte, oligodendrocite, microglia, and endothelial cells. Changes in the neuroendocrine activities are well documented. In particular modifications and alterations in the hypothalamo-pituitary axis correlates to thyroid, somatotropic, lactotropic, and gonadotropic functions (see Roubertoux and Kerdhule, 2006).
Adult persons with DS may develop by the fifth decade of life neuropathological changes typicals of Alzheimer’s disease (i.e., cortical atrophy, ventricular dilatation, presence of neurofibrillary tangles and senile plaques, reduction of basal forebrain cholinergic neurons). Clinical signs and symptoms of Alzheimer’s disease are noted in 75% of such individuals over 60 years of age, (Nadel, 1994; Roizen and Patterson, 2003).
3. Murine models of Down Syndrome
Based on previous description, it appears that DS is characterized by both genotypic and phenotypic variability, therefore, it is difficult to control for differences among individuals and improbable that all DS phenotypes may be explained by an unique genetic background. It is more reasonable to hypothesize that different genes could differentiallly participate to the DS phenotype determination, including neurological alterations and mental retardation. Moreover, only a few data are available on the anatomical and functional correlates in humans. Therefore, considering the necessity to determine the origin of the abnormalities and to follow their evolution, DS awaits the use of appropriate animal models with the possibility to manipulate their genome, and to study all tissues at different embryonic or postnatal stages.
Comparative genomics has drawn up syntenic maps across species and these maps are well documented for mouse and human genomes. HSA21 is syntenic with three mouse chromosomes: MMU10, MMU16, and MMU17 (Fig.1). About 80% of HSA21 and MMU16 were syntenic and the remaining 20% are syntenic with MMU10 and MMU17 (Hattori et al., 2000).
The first murine model for DS was developed about thirty years ago; other models were subsequently developed and periodically their utility and use were reviewed and discussed from different point of views (i.e. genomics, behavior, pharmacological treatment; see for instance the reviews of Dierssen et al 2001; Davisson et al., 2005; Contestabile et al., 2010).
Overall, there are at least three types of murine models for DS: Single gene model
Several models have been generated by the insertion of extra copies of HSA21 single human genes into the mouse genome: SIM2 (Ema et al., 1999), S100beta (Gerlai et al., 1993), SOD1 (Gahtan et al., 1998), APP (Harris-Cerruti et al., 2004). In this case the working hypothesis is that even one gene may have an effect. However, transgenics for individual genes produced scarce effects and the longer is the triplicate fragment, the greater is the effect (Chabert et al., 2004).
HSA21 inserted genes murine models
These models resulted from the insertion of all or part of HSA21 in the mouse genome (Smith et al., 1995; Shinohara et al., 2001; Branchi et al., 2004; Chabert et al., 2004; O’Doherthy et al., 2005).
MMU Extra copy genes murine models
Numerous models have been developed inserting short or long sequences of murine chromosomes. These models are detailed below.
3.1 Ts16 Mice. Since 1980 and for the larger part of two decades, trisomy 16 mice (Ts16) were the only available model for the study of DS. Ts16 mice were developed using mice with Robertsonian chromosome and a breeding scheme that produce high frequencies of mouse embryos with specific whole chromosome trisomies (Fig.1). They were extensively studied and utilized because they demonstrated many similarities to the DS, at morphological, biochemical, immunological and haematological levels (Epstein et al., 1985). However, an important difference exists between DS and Ts16 mice: a significant proportion of human trisomy 21 fetuses (10%) survive to term, whereas Ts16 mice die shortly after birth (Kola and Hertzog, 1998). It is unclear whether this difference is based on a species difference (i.e. mouse versus human) or whether it is attributable to a gene dosage perturbation of genes not found on human chromosome 21 but found on mouse chromosome 16, that shows sequences synthenic to other human chromosomes (3, 8, 16 and 22). The inability of Ts16 mice to survive is a major limitation of the model, in fact many of the features of the human DS phenotype occur postnatal and sometimes even much later in life.
3.2 Ts65Dn mice. This mutant mouse was produced in order to generate mice trisomic for the syntenic segment of the MMU16 that carries genes of the HSA21 DSCR (Davisson et al., 1990; Davisson et al., 1993). In particular, Ts65Dn mouse carry a triplication of a genomic sequence from Mrpl39 to Znf295 genes (Kahlem et al., 2004) and contains several genes like App, Sod1, Sim2, Mx1 and so on).
Contrary to Ts16, the Ts65Dn mice have a longer life, therefore, they might be studied both during development and in adult age. Young Ts65Dn mice were found to be smaller in size compared to control mice but become obese in adult age (Davisson et al., 1993; Kola and Hertzog, 1998). Ts65Dn females have fewer litters than controls (3-7 instead of 10-12) and they exhibit poor care of offspring. Trisomic male mice are generally sterile, and fertile ones are very rare, thus preventing the development of stable colonies and reducing the impact of the model. However, in a recent study Moore et al. (2010) reported the identification and the selective breeding of rare fertile males from two working colonies of Ts65Dn mice, in this way trisomic offspring can be propagated to produce large cohorts of closely related siblings.
The Ts65Dn mouse shows several behavioral alterations resembling those observed in persons with DS. In fact, these mice have deficits in spatial learning and memory (Reeves et al., 1995; Demas et al., 1996; 1998) and altered sexual and aggressive behavior (Klein et al., 1996). The differences in mating behavior and aggression are indicative of deficits in adaptive behavior and persons with DS have been reported to have a variety of adaptive behavioral deficits (Collacott, 1993). As these impairments in the mating and aggressive behavior of Ts65Dn mice do not appear to be due to sensorimotor deficits (Klein et al., 1996), it has been suggested that these mice may serve as useful animal model for the study of other behavioral abnormalities associated with DS, such as learning and memory impairments (Escorihuela et al., 1995; Reeves et al., 1995; Demas et al., 1996).
3.3 Ts1Cje and Ts2Cje Mice. Ts1Cje mouse is a segmental trisomy mouse in which the non-centromeric end of mouse chromosome 16 was translocated to the mouse chromosome 12 (Sago et al., 1998). Ts1Cje mice contain 85 genes including Sod1, Ets2 and Mx1 genes, but not App gene (Fig.1); this segment corresponds to human 21q22.1 to 22.3; the Sod1 gene was disrupted by the chromosomal breakpoint. Both male and female Ts1Cje mice are fertile and produce 50% of Ts1Cje progeny when crossed to wild-type animals. Ts1Cje mice have survived more than 1 year and are indistinguishable from controls in gross appearance. Despite this, reduction in the dimension of the skulls and a pattern of craniofacial anomalies similar to Ts65Dn mice were demonstrated
(Richtsmeier et al., 2002). Moreover, Ts1Cje mice have distinct learning and behavioral abnormalities. Ts2Cje mouse was generated in 2005 (Villar et al., 2005) after a fortuitous translocation of the Ts65Dn marker chromosome to chromosome 12 and contain App gene.
3.4 Ms1Ts65 Mice. In 2000 Sago and co-worker (Sago et al., 2000) generated a new mutant mouse segmentally trisomic for the region by which Ts1Cje and Ts65Dn differ: the region from App to SOD1 genes in which there are 46 genes, to assess the contribution of this region to the Ts65Dn phenotype. These mice were generated crossing Ts65Dn females to Ts1Cje males and shown a much less severe phenotypic impact than other models.
3.5 Recent models
Starting from 2004 a number of new murine models for DS has been published (see Fig.1), in particular the Ts1Rhr Mice (Olson et al., 2004) trisomic for the DSCR; the MTs1Rhr Mice (Olson et al., 2004) disomic for the DSCR; the Tc1 (O’Doherthy et al., 2005) aneuploid for HSA21; the Dp(10)1Yey/+; Dp(16)1Yey/+; Dp(17)1Yey/+ Mice (Yu et al., 2010) with a full triplication of syntenic fragments of MMU10, MMU16 and MMU17; and the Ts1Yah Mice (Pereira et al.; 2009) that carries genes of the MMU17. Virtually no data on brain circuits are however available for these models, with the exception of Tc1 mice (Galante et al., 2009; Morice et al., 2008; O'Doherty et al., 2005; Sheppard et al., 2011).
4. Alterations of brain circuits
Due to the evident cognitive disabilities found in person with DS, most of murine models listed above have been studied almost exclusively from a behavioral point of view (cognitive and learning tasks; see for recent literature Seregaza et al., 2006; Roubertoux and Carlier, 2010). Very little is known about possible neurochemical impairments in the brain of these strains and investigations on the alterations of neuronal circuits in murine models converged principally to MMU16 extra copy genes models. From this point of
view Ts65Dn and Ts1Cje mice are the most studied models (see tables 1-2). Generally, these studies were directed to brain structural alterations or neurotransmitter/neuropeptide systems’ modifications.
4.1 Cholinergic system
The degeneration of basal forebrain cholinergic neurons is a typical hallmark observed in persons with DS and Alzheimer disease (Yates et al., 1983; Casanova et al., 1985), therefore, several investigations involved the cholinergic system of Ts65Dn mice (see table 1). In postnatal developmental studies a loss of cholinergic neurons in the medial septal nucleus and in the diagonal band of Broca, was observed (comparing Ts65Dn male mice at 4, 6, 8 and 10 months of age) starting from 6 month-old mice, the same age in which began the cognitive decline (Granholm et al., 2000). Other studies reported a much more delayed degeneration: 12 months (comparing Ts65Dn male mice of 4 and 12 months, Seo and Isacson, 2005;), or 18 months in Ts65Dn female mice (Hunter et al., 2004). At the age of 6 months several studies observed a reduction in the number of p75-NGFR- (a low affinity NGF receptor, localized in cholinergic neurons) and trkA- (a high-affinity NGF receptor) immunoreactive neurons of medial septal nucleus (Holtzman et al., 1996; Granholm et al., 2000; Cooper et al., 2001; Salehi et al., 2006) . The evaluation of choline acetyltransferase (ChAT) activity in other brain regions like hippocampus, olfactory bulb, olfactory cortex, pre-frontal cortex, and cerebellum, but not in other neocortical regions, demonstrated an up-regulation of the enzyme activity starting from the age of 10 months in Ts65Dn mice (Seo and Isacson, 2005; Contestabile et al., 2006). Remarkably, Ts1Cje mouse, although shows severe cognitive impairments, does not have degeneration of basal cholinergic forebrain neurons seen in Ts65Dn mouse (Sago et al., 1998).
4.2 Monoaminergic systems
Serotonergic system is altered in adult individuals with DS; this finding may be relevant to the pathogenesis and treatment of cognitive and non-cognitive (behavioral) features in DS (Seidl et al., 1999), therefore this system was investigated in Ts65Dn mice. However, a study performed in 3 month-old Ts65Dn mice found no alterations in the serotonergic
as well as in the catecholaminergic systems [identified by tyrosine hydroxylase (TH) immunoreactivity, Megias et al., 1997]. Interestingly, in this investigation no differences were found also in the cholinergic system, confirming that this system is altered later in life (Granholm et al., 2000). No subsequent investigations of TH or serotonin systems were performed in adults Ts65Dn or in other DS models.
Some studies were dedicated to the noradrenergic system that is involved in attentional and cognitive processes. In 5 month-old Ts65Dn mice, the central noradrenergic transmission, in particular the adenylate cyclase activity, was altered in the hippocampus and cerebral cortex, but not in other brain regions (Dierssen et al., 1997). A recent study reported that 8 month-old Ts65Dn mice exhibit progressive loss of norepinephrine phenotype in neurons of the Locus coeruleus, thus mimicking the early loss of locus coeruleus neurons in AD and in DS, that may contribute to these neuropathologies (Lockrow et al., 2011).
4.3 Nitrergic system
Nitric oxide (NO) is a gaseous neurotransmitters produced by the nitric oxide synthase (NOS) enzyme. NO is implicated in the control of several behaviors like aggressive and sexual behavior: for example, elevated aggressive behavior was reported in mice lacking the gene for neural isoform of NOS (Nelson et al., 1995). Several of the NO-related behaviors are altered in both persons with DS and in Ts65Dn mice, suggesting a possible involvement of nNOS-derived NO in DS. In a first study we demonstrated that Ts65Dn mice show both an increase of aggressive behavior and a precocious reduction of nitrergic neurons in the basal forebrain nuclei and in the hypothalamic paraventricular nucleus (PVN) at 3 months of age (Gotti et al., 2004; Fig.2) indicating a clear correlation of the behavioral aggressiveness with deficient NO production. The alteration of nNOS system is selective and don’t involve the whole nitrergic system; in fact other regions, as the pontine tegmental nuclei don’t show alterations of both nitrergic and cholinergic systems (Gotti et al., 2005). Tegmental nuclei are connected to the vertical part of the diagonal band of Broca (VDB) and medial septum (MS) and are important to start and stop locomotion; they represent a major mesopontine cholinergic system. Nitrergic and cholinergic systems are functionally related (de Vente, 2004), however the degree of
co-localization is variable in different brain regions. In our study (Gotti et al., 2005) we demonstrated a high degree of co-localization in pontine tegmental nuclei, whereas, in VDB-MS there is a low degree of co-localization (Fig.2). Noteworthy, at the age of 3 months the nitrergic system is altered only at the level of basal forebrain, while the cholinergic system is not altered (both in the basal forebrain, and in the mesopontine system). As previously reported, the cholinergic system starts its degeneration at later age (6 months, see Granholm et al., 2000) in VDB-MS, and no sign of degeneration have been reported for the mesopontine system. Therefore, it seems that the high degree of co-localization may represent a protective factor for the degeneration of neural circuits (mesopontine region), while in the basal telencephalon the precociuos alterations of nitrergic system could be causally related to the subsequent degeneration of the cholinergic system detected in basal forebrain of older animals.
4.4 Vasopressinergic system
Data collected in patients with DS demonstrated alterations in osmoregulation and autonomic functions, and indicated the vasopressinergic system of PVN as the major locus responsible of these changes (Mann et al., 1985; Labudova et al., 1998). Therefore, we investigated the distribution of arginine-vasopressin (AVP) immunoreactivity in the PVN of aged Ts65Dn female mice. The number of AVP immunoreactive neurons was significantly reduced in mutants as compared to controls (Panzica et al., 2006); therefore it seems that the AVP producing hypothalamic magnocellular system is one of major targets of the DS. On the other hand, AVP changes could reflect derangement of the adrenergic neurotransmitter system as the interaction between AVP and adrenergic neurons was proposed in literature (Labudova et al., 1998).
5. Structural alterations of the brain
As reported in the introduction, individuals with DS show several brain structural alterations in different regions. Similar studies have been performed in both Ts65Dn and Ts1Cje mice illustrating macro- and microscopical changes in the hippocampus and cortex (table 2).
5.1 Hippocampus
Starting from post-natal day 2, in Ts65Dn mice, it was observed a reduction of both hippocampal volume and cell proliferation (Contestabile et al., 2007). Moreover, at post-natal day 21 Ts65Dn mice show a reduction of hippocampal spine density (Belichenko et al., 2004) and, at 2 months of age, an alteration of neurogenesis (Clark et al., 2006). Also the electrical properties of hippocampus are altered, in fact, it was observed a reduction of long-term potentation (LTP) and an increase in long-term depression (LTD) in CA1 and DG regions (Siarey et al., 1999; Belichenko et al., 2007). In Ts1Cje and Ts1Rhr mice the decrease of hippocampal spine density was observed at 6 months of age (Belichenko et al., 2007, 2009). A reduction of neurogenesis within the subventricular zone of the lateral ventricle and of the hippocampal DG was found also in Ts1Cje mice at 3 months of age (Ishihara et al., 2010).
5.2 Cortex, cerebellum, and lateral ventricles
Development of the neocortex of the Ts16 mouse is characterized by a transient delay in the radial expansion of the cortical wall and a persistent reduction in cortical volume (Haydar et al., 1996). This is due to altered proliferative characteristics during Ts16 neuronogenesis and it results in a delay in the generation of neocortical neurons, leading to significant neocortical abnormalities such as those found in humans with DS (Haydar et al., 2000).
Pyramidal cells in environmentally enriched control animals become significantly more branched and more spinous than non-enriched controls. However, environmental enrichment had little effect on pyramidal cell structure in Ts65Dn mice. Differences in the number of spines found in the dendritic arbors of pyramidal cells in the two groups reflect differences in the number of excitatory inputs they receive and, consequently, complexity in cortical circuitry. These results suggest that behavioral deficits demonstrated in the Ts65Dn model could be attributed to abnormal circuit development (Dierssen et al., 2003). In addition, Ts65Dn mice show an increase of synaptophysin levels and calcium binding protein immunoreactive neurons from 4 months of age (Pérez-Cremades et al., 2010), and, starting from the age of 12 months, there is an increase of
VIP-immunoreactive neurons and of APP protein levels (Hill et al., 2003; Hunter et al., 2003). Other studies were performed in Ts1Cje mice demonstrating oxidative stress, mitochondrial dysfunction and hyperphosphorylation of tau, all of which may play critical roles in the pathogenesis of mental retardation in DS (Shukkur et al., 2006). Altered regulation of tau phosphorylation was also observed in Tc1 mice (Sheppard et al., 2011).
The whole size of the cerebellum and the number of granule cells was reduced very early in Ts65Dn mice (Roper et al., 2006; Aldridge et al., 2007; Baxter et al., 2000), as well as in Ts1Cje (Olson et al., 2004) and in Tc1 (O'Doherty et al., 2005). In particular, Tc1 mice revealed motor behavior alterations that may be related to cerebellar circuits alteration (Galante et al., 2009).
In recent studies it was observed a general reduction of the volume of ventricles in Ts65Dn mice (Bianchi et al., 2010a) and an enlargement of ventricles’ size in Ts1Cje mice (Ishihara et al., 2010).
6. Concluding remarks
DS is a complex disease and the mechanisms by which it produces phenotypic abnormalities are not fully understood (Dierssen et al., 2001; Antonarakis and Epstein, 2006). As explained in the introduction, in spite of many biochemical and physiological studies of the DS, it is still not fully known how the individual genes on HSA21, either singly or in association produce the phenotypical and behavioral alterations associated with the DS.
The number of murine models of DS is rapidly increasing. They have been generated, using different strategies (i.e., single gene, HSA21 inserted genes, or MMU extra copy genes models), but they are in some way under-used and scarcely known. These murine models provided a lot of new insights about cognitive impairments and disabilities and the possible correlation with a triplication of some genes. Nevertheless, detailed descriptions of neural circuits alterations and the comparison with those observed in the brain of humans with DS is still sporadic and not systematic, with the exception of the cholinergic system.
Changes in the size of the whole brain, of the cerebellum, and of the ventricles have been well documented in humans with DS and in Ts65Dn mice and other models (see table 2). Losses of brain functions, decreased levels of specific proteins, and alterations of brain circuits have also been discovered in trisomic mice, but there are serious gaps in the possible comparisons. For example: in DS brains (as well as in Alzheimer patients), gliosis and astrocytosis are frequently observed (Griffin et al., 1989). This is probably due to an overexpression of S100 beta gene (located in the DSCR of HSA21) that codes for S100, a calcium binding protein highly expressed in astrocytes, but also in cerebral neurons (Rickmann and Wolff, 1995; Castagna et al., 2003). In Ts65Dn mice there is no gliosis or astrocytes alteration, probably because the S100beta gene is located in mouse chromosome 10 and is not triplicated in this strain. The recent models in which there is a triplication of all syntenic genes of chromosome 10, 16 and 17 (Yu et al., 2010) could be very important for this point of view; unfortunately, this model was studied only for behavioral profiles. Another example is the Ts1Yah mice: the triplication of the genes of chromosome 17 in this case is not inducing cognitive impairment (Pereira et al., 2009) but nothing is known about the general brain morphology of this model.
At the moment, the Ts65Dn mouse is the only strain that have been investigated in details for behavioral deficits, neural circuits and brain structural alterations (see table 1-2). The earliest signal of brain circuits’ alteration in these mutant mice is represented by a decrease in the cell proliferation during the first week of life in the hippocampus (Contestabile et al., 2007), followed by the decrease of neurogenesis in the hippocampus at 2 months of life (Clark et al., 2006). In the basal forebrain, the nitrergic system shows a significant decrease of cell number at the age of 3 months (Gotti et al., 2004), followed by alteration of the noradrenergic transmission at the age of 5 months (Dierssen et al., 1997), and by the descrease of the cholinergic system at the age of 6 months (Granholm et al., 2000) or later (Seo and Isacson, 2005). These data, together with those collected at molecular level (Antonarakis and Epstein, 2006) could be very useful to understand the genesis of DS and provide hypothetical possibilities for exogenous correction of altered gene expression in DS.
However, present knowledge of the molecular pathogenesis of DS is poor, and the murine models have been largely used for descriptive and not for experimental purposes.
An overall analysis and comparative study of the existing models should be considered, but mice should be on the same genetic background and protocols should cover every aspect of mouse neurological, behavioral, biochemical, and histopathological features. Present descriptions are lacking of several details, for example studies comparing directly male and female expression of different markers are missing, many models have been studied only for their behavioral alterations and very few post-mortem neurochemical analyses in DS brain has been performed in order to validate and confirms data observed in murine models. The hope for the future is that the large amount of knowledge accumulated for some of the murine models (e.g. Ts65Dn mice) could be soon utilized to have a better understanding of the DS. In a complex disease like DS even each little “tessera” would be very important for the comprehension of the entire story.
Acknowledgements
This study was supported by University of Torino, Regione Piemonte and Cavalieri-Ottolenghi Foundation, Italy
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Figure legends
Figure 1. Mouse models of trisomy 21. Human chromosome 21 (HSA21) is presented
with syntenic regions on mouse chromosomes (MMU16, MMU17, MMU10). The length of the bar is proportional to the number of genes carried by the fragment. (Partially modified from Seregaza et al., 2006; Roubertoux and Carlier, 2010).
Figure 2. Nitrergic system in basal forebrain, hypothalamus and mesopontine regions of
Ts65Dn mice: comparison with wild type ad co-localization with the cholinergic system.
Top panels: photomicrographs of sections at the level of the vertical part of the diagonal
band of Broca (VDB); middle panels: photomicrographs of sections at the level of the paraventricular hypothalamic nucleus (PVN). Nitrergic neurons are detected by means of immunohistochemistry for the enzyme n-NOS (NOS) or by histochemistry for NADPH-Diaphorase (ND). With both methods it is possible to note a dramatic reduction of the number of positive neurons in the trisomic (TS) mice compared to control (WT) mice.
Bottom panels: ChAT-ND double staining illustrating low co-localization in medial
septum (MS) and VDB, no co-localization in caudate-putamen complex (CPu) and high degree of co-localization in laterodorsal tegmental nucleus (LDT). Brown-orange cells: ChAT postive elements; Blu-violet cells: NADPH-Diaphorase positive elements; black cells: ChAT-ND double stained cells. Magnification bars = 150 µm in top and middle panels; 300 µm in double staining for MS-VDB and CPu; 150 µm in double staining for LDT. For methods see Gotti et al., 2004; Panzica and Garzino, 1997.
Table 1. Neurotransmitters’ systems altered in Ts65Dn mouse. Data are collected
according to different systems and different regions.
Table 2. Structural alterations and changes in neurogenesis in different trisomic models.
Left column reports the trisomic model. The changes are collected according to the different regions.
brain area and type of investigations
Comparison
TS Vs. Eu Age Sex References
CHOLINERGIC SYSTEM
MEDIAL SEPTAL NUCLEUS
6 months ns Holtzman et al. (1996)
number of p75-NGFR-ir neurons TS<Eu 12 months M Cooper et al. (2001)
19 months M Salehi et al. (2006)
ChAT-ir cell size TS<Eu 8 months M Granholm et al. (2000)
6 months M Granholm et al. (2000)*
number of ChAT-ir neurons TS<Eu 12 months ns Seo and Isacson (2005)
18 months F Hunter et al. (2004)
cell size and density of trkA-ir neurons TS<Eu 6 months M Granholm et al. (2000)
cell size and number of TrkA-ir neurons 19 months M Salehi et al. (2006)
BASAL FOREBRAIN
NGF protein levels TS<Eu 9 months F Hunter et al. (2003)
HIPPOCAMPUS
ChAT enzyme activity TS>Eu 10 monthsM and F Contestabile et al. (2006)
12 months ns Seo and Isacson (2005)
CEREBELLUM
ChAT enzyme activity TS>Eu 10 monthsM and F Contestabile et al. (2006)
NORADRENERGIC SYSTEM
CORTEX
basal level of cAMP TS<Eu 5 months ns Dierssen et al. (1997)
HIPPOCAMPUS
basal level of cAMP TS<Eu 5 months ns Dierssen et al. (1997)
LOCUS COERULEUS
loss of norepinephrine phenotype in neurons TS>Eu 8 months ns Lockrow et al. (2011)
NITRERGIC SYSTEM
number of NOS-ir neurons TS<Eu 3 months M Gotti et al. (2004)
PARAVENTRICULAR NUCLEUS
number of NOS-ir neurons TS<Eu 3 months M Gotti et al. (2004)
PEPTIDERGIC SYSTEMS
PARAVENTRICULAR NUCLEUS
number of vasopressin-ir neurons TS<Eu 18 months F Panzica et al. (2006)
HIPPOCAMPUS
VIP-ir neurons TS>Eu 12 months M Hill et al. (2003)
* also in Ventral part of the Diagonal band of Broca
Mouse model brain area and type of investigations
Comparison
TS Vs. Eu Age Sex References
STRUCTURAL ALTERATIONS
MEDIAL SEPTAL NUCLEUS
Ts65Dn enlarged endosome TS>Eu 6 months M and F Cataldo et al. (2003)
microglial activation (CD45-ir) TS>Eu 18 months F Hunter et al. (2004)
LATERAL VENTRICLES
Ts65Dn volume and lenght TS<Eu 12 months F Bianchi et al. (2010b)
Ts1Cje size TS>Eu PD12 M Ishihara et al. (2010)
CORTEX
Ts65Dn GAD-67, CB, CR, PV immunoreactivity in somatosensory synaptophysin levels in somatosensory cortex TS>Eu 4 months M Pérez-Cremades et al. (2010) cortex
BDNF protein in frontal cortex 6 months M Bimonte-Nelson et al. (2003)
dendritic arbors size of pyramidal cells TS<Eu 12 months F Dierssen et al. (2003)
branching pattern and dendritic lenght of pyramidal cells
VIP-ir neurons TS>Eu 12 months M Hill et al. (2003)
APP protein levels 13 months F Hunter et al. (2003)
CEREBELLUM
Ts65Dn size and number of granule cell (GC) PD6 ns Roper et al. (2006)
whole size TS<Eu 3 months ns Aldridge et al. (2007)
internal granule layer (IGL) and moleculare layer (ML) 4 months M and F Baxter et al. (2000)
Purkinje cells axonal alterations TS>Eu 10 months Necchi et al. (2008)
ML and IGL thickness and cell density TS<Eu ns
death of Punkinje cells TS>Eu 12 months ns Lomoio et al. (2009)
Ts1Cje volume and granule cells density TS<Eu 2,5 monthsM and F Olson et al. (2004)
Tc1 granule cells density TS<EU ns M O'Doherthy et al. (2005)
HIPPOCAMPUS
Ts65Dn volume of GCL PD2 ns Contestabile et al. (2007)
number and density of granule cells in DG TS<Eu PD6 M Lorenzi and Reeves (2006)
spine density PD21 M Belichenko et al. (2004)
size of Presynaptic terminals and dendritic spines TS>Eu
presence of EEs that contain NGF and App TS>Eu 3 months M Salehi et al. (2006)
synaptophysin levels TS<Eu 4 months ns Pollonini et al. (2008)
NT3 and CDK5 levels TS>Eu
CB-ir neurons in CA1/CA2 regions TS<Eu 4 months M Lockrow et al. (2009)
10 months M Hunter et al. (2004)
mean neuron number in granule cell layer (GCL) of DG TS<Eu 5 months ns Insausti et al. (1998)
mean neuron number in granule cell layer (GCL) of CA3
TS>Eu 5 months ns
NGF protein levels TS>Eu 6 months M Cooper et al. (2001)
TS<Eu 13 months F Hunter et al. (2003)
beta amyloid levels TS>Eu 6 months M Hunter et al. (2004b)
immunolabeling for Map2 in CA1 and DG TS<Eu 9 months F Granholm et al. (2003)
APP protein levels TS>Eu 13 months F Hunter et al. (2003)
microglial activation (CD45-ir) TS>Eu 18 months F Hunter et al. (2004)
Ts1Cje DSCAM levels in neurons TS>Eu adults (ns) ns Alves-Sampaio et al. (2010)
LPO-derived products TS>Eu 3 months M Ishihara et al. (2009)
spine density TS<Eu 6 months M Belichenko et al. (2007)
Ts1Rhr spine density TS<Eu 6 months M Belichenko et al. (2009)
STRIATUM
Ts65Dn APP protein levels TS>Eu 6 months F Hunter et al. (2003)
WHOLE BRAIN
Ts65Dn levels of MAP2 and NT3 TS>Eu PD1 ns Pollonini et al. (2008)
