Neonatal therapy with clenbuterol and salmeterol restores spinogenesis and dendritic complexity in the dentate gyrus of the Ts65Dn model of Down syndrome

Emili, Marco; Stagni, Fiorenza; Salvalai, Maria Elisa; Uguagliati, Beatrice; Giacomini, Andrea; Albac, Christelle; Potier, Marie‐Claude; Grilli, Mariagrazia; Bartesaghi, Renata; Guidi, Sandra

doi:10.1016/j.nbd.2020.104874

Cited by 14 publications

(17 citation statements)

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“…Spine density reduction is a typical feature of the dendritic pathology that affects the brain of infants with DS (Takashima et al, 1981). Defects in spine density have been also observed in the dentate gyrus of the Ts65Dn mouse model aged 15 days (Emili et al, 2020; Stagni et al, 2017; Stagni et al, 2019). There is no information, however, regarding the onset of this defect.…”

Section: Resultsmentioning

confidence: 94%

“…Most of the granule cells of the dentate gyrus are adult‐like by day 14 (Jones, Rahimi, O'Boyle, Diaz, & Claiborne, 2003; Rihn & Claiborne, 1990). Therefore, we deemed it of interest to compare the dendritic architecture of P8 euploid and Ts65Dn mice with our previous data on the dendritic architecture of euploid and Ts65Dn mice aged 15 days, an age at which numerous defects are present in Ts65Dn mice (Emili et al, 2020). We first compared the number of segments and the total length of the dendritic tree.…”

Section: Resultsmentioning

confidence: 99%

“…Euploid and Ts65Dn male mice were killed at postnatal day 8 (P8) and 15 (P15). The P15 mice were the same used in a previous study (Emili et al, 2020). Additional P15 mice were used for the study of spine morphology.…”

Section: Methodsmentioning

confidence: 99%

“…Unfortunately, there is a strikingly paucity of studies that have characterized in depth the time course of dendritic alterations in the hippocampus (and other brain regions) of individuals with DS and even fewer studies in the Ts65Dn model. It is known that the granule cells of the hippocampal dentate gyrus of Ts65Dn mice exhibit defects in dendritic complexity and dendritic spine density in adulthood (Belichenko et al, 2004; Dang et al, 2014; Guidi et al, 2013; Stagni et al, 2015) and that these defects are already present in mice aged 15 days (Emili et al, 2020; Stagni et al, 2017; Stagni et al, 2019). The onset of these defects, however, remains to be established.…”

Section: Introductionmentioning

confidence: 99%

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Early appearance of developmental alterations in the dendritic tree of the hippocampal granule cells in theTs65Dnmodel of Down syndrome

et al. 2021

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Down syndrome (DS), a genetic condition caused by triplication of chromosome 21, is characterized by alterations in various cognitive domains, including hippocampus‐dependent memory functions, starting from early life stages. The major causes of intellectual disability in DS are prenatal neurogenesis alterations followed by impairment of dendritic development in early infancy. While there is evidence that the Ts65Dn mouse, the most widely used model of DS, exhibits dendritic alterations in adulthood, no studies are available regarding the onset of dendritic pathology. The goal of the current study was to establish whether this model exhibits early dendritic alterations in the hippocampus, a region whose function is severely damaged in DS. To this purpose, in Golgi‐stained brains, we evaluated the dendritic arborization and dendritic spines of the granule cells of the hippocampal dentate gyrus in Ts65Dn mice aged 8 (P8) and 15 (P15) days. While P15 Ts65Dn mice exhibited a notably hypotrophic dendritic arbor and a reduced spine density, P8 mice exhibited a moderate reduction in the number of dendritic ramifications and no differences in spine density in comparison with their euploid counterparts. Both in P8 and P15 mice, spines were longer and had a longer neck, suggesting possible alterations in synaptic function. Moreover, P8 and P15 Ts65Dn mice had more thin spines and fewer stubby spines in comparison with euploid mice. Our study provides novel evidence on the onset of dendritic pathology, one of the causes of intellectual disability in DS, showing that it is already detectable in the dentate gyrus of Ts65Dn pups. This evidence strengthens the suitability of this model of DS as a tool to study dendritic pathology in DS and to test the efficacy of early therapeutic interventions aimed at ameliorating hippocampal development and, therefore, memory functions in children with DS.

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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Early appearance of developmental alterations in the dendritic tree of the hippocampal granule cells in theTs65Dnmodel of Down syndrome

et al. 2021

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“…Adrenergic agonism has been shown to be effective in supporting the proliferation of granule cells in the dentate [149][150][151] . Indeed, very recent data has shown that neonatally treating Ts65Dn mice with a beta-2 adrenergic agonist successfully restores normal dendritic development in hippocampal granule cells 150 , suggesting that a prolonged lack of normal connectivity produces the abnormal dendritic arborization. Interestingly, this prophylactic treatment does not rectify the abnormal neurogenesis in the Ts65Dn model, although beta-2 agonism was shown to increase neural proliferation in vitro.…”

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confidence: 99%

Signalling pathways contributing to learning and memory deficits in the Ts65Dn mouse model of Down syndrome

Freeburn

Munn

2021

Neuronal Signaling

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Down syndrome (DS) is a genetic trisomic disorder that produces life-long changes in physiology and cognition. Many of the changes in learning and memory seen in DS are reminiscent of disorders involving the hippocampal/entorhinal circuit. Mouse models of DS typically involve trisomy of murine chromosome 16 is homologous for many of the genes triplicated in human trisomy 21, and provide us with good models of changes in, and potential pharmacotherapy for, human DS. Recent careful dissection of the Ts65Dn mouse model of DS has revealed differences in key signalling pathways from the basal forebrain to the hippocampus and associated rhinal cortices, as well as changes in the microstructure of the hippocampus itself. In vivo behavioural and electrophysiological studies have shown that Ts65Dn animals have difficulties in spatial memory that mirror hippocampal deficits, and have changes in hippocampal electrophysiological phenomenology that may explain these differences, and align with expectations generated from in vitro exploration of this model. Finally, given the existing data, we will examine the possibility for pharmacotherapy for DS, and outline the work that remains to be done to fully understand this system.

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

López-Hidalgo,

Ballestín,

Lorenzo

et al. 2024

Neurochemistry International

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Neonatal therapy with clenbuterol and salmeterol restores spinogenesis and dendritic complexity in the dentate gyrus of the Ts65Dn model of Down syndrome

Cited by 14 publications

References 61 publications

Early appearance of developmental alterations in the dendritic tree of the hippocampal granule cells in theTs65Dnmodel of Down syndrome

Early appearance of developmental alterations in the dendritic tree of the hippocampal granule cells in theTs65Dnmodel of Down syndrome

Signalling pathways contributing to learning and memory deficits in the Ts65Dn mouse model of Down syndrome

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

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