Excitatory‐inhibitory relationship in the fascia dentata in the Ts65Dn mouse model of down syndrome

Belichenko, Pavel V.; Kleschevnikov, Alexander M.; Masliah, Eliezer; Wu, Chengbiao; Takimoto-Kimura, Ryoko; Salehi, Ahmad; Mobley, William C.

doi:10.1002/cne.21895

Cited by 134 publications

(166 citation statements)

References 38 publications

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“…Previous studies have pointed a higher level of inhibition in some regions of the neocortex and the hippocampus (Belichenko et al 2004(Belichenko et al , 2007(Belichenko et al , 2009Kurt et al 2000). In this sense, treatment with picrotoxin (a GABA A receptor antagonist), improves behavioural performance (Fernandez et al 2007).…”

Section: Discussionmentioning

confidence: 96%

Alteration of inhibitory circuits in the somatosensory cortex of Ts65Dn mice, a model for Down’s syndrome

et al. 2010

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Down's syndrome (DS), with an incidence of one in 800 live births, is the most common genetic disorder associated with mental retardation. This trisomy on chromosome 21 induces a variable phenotype in which the only common feature is the presence of mental retardation. The neural mechanisms underlying mental retardation might include defects in the formation of neuronal networks and neural plasticity. DS patients have alterations in the morphology, the density and the distribution of dendritic spines in the pyramidal neurons of the cortex. Our hypothesis is that the deficits in dendritic arborization observed in the principal neurons of DS patients and Ts65Dn mice (a model for DS that mimics most of the structural alterations observed in humans) may be mediated to some extent by changes in their inhibitory inputs. Different types of interneurons control different types of inhibition. Therefore, to understand well the changes in inhibition in DS, it is necessary to study the different types of interneurons separately. We have studied the expression of synaptophysin, Glutamic acid decarboxylase-67 (GAD-67) and calcium-binding protein-expressing cells in the primary somatosensory cortex of 4-5 month old Ts65Dn mice. We have observed an increment of GAD67 immunoreactivity that is related mainly to an increment of calretinin-immunoreactive cells and among them the ones with bipolar morphology. Since there is a propensity for epilepsy in DS patients, this increase in interneurons might reflect an attempt by the system to block overexcitation rather than an increment in total inhibition and could explain the deficit in interneurons and principal cells observed in elderly DS patients.

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Section: Discussionmentioning

confidence: 96%

Alteration of inhibitory circuits in the somatosensory cortex of Ts65Dn mice, a model for Down’s syndrome

et al. 2010

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“…These include a reduction in the numbers of neurons and dendritic spines, dendritic arborization, an alteration in the excitatory-inhibitory balance and a global impairment in network connectivity 68,[162][163][164][165][166] . These perturbations in the structure, function and organization of the CNS may profoundly affect its degeneration in AD-DS (BOX 1).…”

Section: Neuronal Development and Functionmentioning

confidence: 99%

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

et al. 2015

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Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP) -an Alzheimer disease risk factor -although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.Down syndrome (DS) is a complex, highly variable disorder that arises from trisomy of chromosome 21. It was one of the first chromosomal disorders to be identified 1 and occurs with an incidence of approximately 1 in 800 births 2 . Its prevalence within a given population is influenced by infant mortality rates, access to health care, termination rates, average maternal age 3 and life expectancy. Indeed, despite the increased availability of prenatal diagnosis and access to the option of termination, the global prevalence of DS is rising because of improvements in life expectancy: the number of adults with DS aged over 40 years has doubled in northern Europe since 1990 and, in the United Kingdom, one-third of the estimated 40,000 people with DS are thought to be over 40 years of age 4 .DS is the most common form of intellectual disability. In addition to the features that are found in everyone with the disorder, such as the characteristic facial dysmorphology, there are many DS-associated phenotypes that have variable penetrance and severity. For example, approximately 40% of individuals with DS have heart malformations (usually atrioventricular septal defects) 5 . A key feature of DS is a striking propensity to develop early-onset Alzheimer disease (EOAD). Complete trisomy of chromosome 21 universally causes the development of amyloid plaques and neurofibrillary tangles (NFTs), which are typical characteristics of AD brain pathology, by the age of 40, and approximately twothirds of individuals with DS develop dementia by the age of 60 (REFS 6,7). However, rates of dementia do not reach 100%, even in older individuals, suggesting that some individuals with DS are protected from the onset of AD (FIG. 1).All of the features of DS arise because of aberrant dosages of coding and/or non-coding sequences present on chromosome 21. Among these sequences, the gene encoding amyloid precursor protein (APP) is thought to have a key role in the pathology of AD. The additional copy of APP may drive the development of AD in individuals with DS (AD-DS) by increasing the levels of amyloid-β (Aβ), a cleavage product of APP that misfolds and accumulates in the brain in people with AD. Consistent with this hypothesis, individuals with small internal chromosome 21 duplications that result in three copies of APP -a rare familial trait known as duplic...

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“…The Ts(17 16 )65Dn mouse (Ts65Dn), the most widely used and well-characterized model in the study of DS, has a small trisomic chromosome that triplicates about half of the gene orthologs found on Hsa21 (Reeves et al, 1995;Sturgeon & Gardiner, 2011). Ts65Dn mice exhibit many of the central nervous system (CNS) phenotypes related to cognitive impairment in DS including abnormal dendritic spine density and structure, altered hippocampal structure with reduced number of neurons in the dentate gyrus and CA3 regions, and severe reductions in LTP (Belichenko et al, 2009;Belichenko, Kleschevnikov, Salehi, Epstein, & Mobley, 2007;Belichenko et al, 2004;Insausti et al, 1998;Kleschevnikov et al, 2004). Ts65Dn mice also show a reduction in cerebellum size, as well as the number of cerebral granule cells (Baxter, Moran, Richtsmeier, Troncoso, & Reeves, 2000).…”

Section: Individuals With Ds Display Developmental Alterations In Bramentioning

confidence: 99%

Low dose EGCG treatment beginning in adolescence does not improve cognitive impairment in a Down syndrome mouse model

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Abeysekera

Dria

et al. 2015

Pharmacology Biochemistry and Behavior

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Excitatory‐inhibitory relationship in the fascia dentata in the Ts65Dn mouse model of down syndrome

Cited by 134 publications

References 38 publications

Alteration of inhibitory circuits in the somatosensory cortex of Ts65Dn mice, a model for Down’s syndrome

Alteration of inhibitory circuits in the somatosensory cortex of Ts65Dn mice, a model for Down’s syndrome

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

Low dose EGCG treatment beginning in adolescence does not improve cognitive impairment in a Down syndrome mouse model

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