Mouse Models of Neurodevelopmental Disease of the Basal Ganglia and Associated Circuits

Pappas, Samuel S.; Leventhal, Daniel K.; Albin, Roger L.; Dauer, William T.

doi:10.1016/b978-0-12-397920-9.00001-9

Cited by 35 publications

(20 citation statements)

References 421 publications

(578 reference statements)

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“…To identify the molecular pathways that disrupt CNS maturation in N-CKO mice in an unbiased manner, we conducted global gene expression analyses on striatum and cortex–two brain regions central to motor control and strongly implicated in dystonia pathogenesis (Liang et al, 2014; Pappas et al, 2015; Pappas et al, 2014; Tanabe et al, 2009). We performed microarray analyses comparing control and N-CKO RNA from these regions at P21, the age when motor deficits are emerging (GEO accession number: GSE97372).…”

Section: Resultsmentioning

confidence: 99%

The DYT6 Dystonia Protein THAP1 Regulates Myelination within the Oligodendrocyte Lineage

et al. 2017

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SUMMARY The childhood-onset motor disorder DYT6 dystonia is caused by loss-of-function mutations in the transcription factor THAP1, but the neurodevelopmental processes in which THAP1 participates are unknown. We find that THAP1 is essential for the timing of myelination initiation during CNS maturation. Conditional deletion of THAP1 in the CNS retards maturation of the oligodendrocyte (OL) lineage, delaying myelination and causing persistent motor deficits. The CNS myelination defect results from a cell autonomous requirement for THAP1 in the OL lineage, and is recapitulated in developmental assays performed on OL progenitor cells purified from Thap1 null mice. Loss of THAP1 function disrupts a core set of OL maturation genes and reduces the DNA occupancy of YY1, a transcription factor required for OL maturation. These studies establish a role for THAP1 transcriptional regulation at the inception of myelination, and implicate abnormal timing of myelination in the pathogenesis of childhood-onset dystonia.

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Section: Resultsmentioning

confidence: 99%

The DYT6 Dystonia Protein THAP1 Regulates Myelination within the Oligodendrocyte Lineage

et al. 2017

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“…The selection of goal‐directed actions is governed by associations between the value of the consequences and is sensitive to changes in the causal relationship between the action and those consequences whereas habituation actions are controlled through stimulus‐response associations without the association with the value of the outcome (Griffiths, Morris, & Balleine, ). Imbalances between goal‐directed and habitual action are observed in many neurological disorders including Parkinson's disease, Tourette Syndrome and obsessive‐compulsive disorder (Gillan & Robbins, ; Pappas, Leventhal, Albin, & Dauer, ; Redgrave et al., ) so these results may indicate a broad therapeutic benefit of CAW beyond age‐related cognitive impairment. It would be interesting in future studies to see if similar effects are seen in young animals.…”

Section: Discussionmentioning

confidence: 99%

Centella asiatica increases hippocampal synaptic density and improves memory and executive function in aged mice

et al. 2018

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Introduction Centella asiatica is a plant used for centuries to enhance memory. We have previously shown that a water extract of Centella asiatica (CAW) attenuates age‐related spatial memory deficits in mice and improves neuronal health. Yet the effect of CAW on other cognitive domains remains unexplored as does its mechanism of improving age‐related cognitive impairment. This study investigates the effects of CAW on a variety of cognitive tasks as well as on synaptic density and mitochondrial and antioxidant pathways.MethodsTwenty‐month‐old CB6F1 mice were treated with CAW (2 mg/ml) in their drinking water for 2 weeks prior to behavioral testing. Learning, memory, and executive function were assessed using the novel object recognition task (NORT), object location memory task (OLM), and odor discrimination reversal learning (ODRL) test. Tissue was collected for Golgi analysis of spine density as well as assessment of mitochondrial, antioxidant, and synaptic proteins.ResultsCAW improved performance in all behavioral tests suggesting effects on hippocampal and cortical dependent memory as well as on prefrontal cortex mediated executive function. There was also an increase in synaptic density in the treated animals, which was accompanied by increased expression of the antioxidant response gene NRF2 as well as the mitochondrial marker porin.ConclusionsThese data show that CAW can increase synaptic density as well as antioxidant and mitochondrial proteins and improve multiple facets of age‐related cognitive impairment. Because mitochondrial dysfunction and oxidative stress also accompany cognitive impairment in many pathological conditions this suggests a broad therapeutic utility of CAW.

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“…Therapeutic benefit from antimuscarinic drugs ( Burke et al, 1986 ) also implicates striatal dysfunction, as striatal cholinergic interneurons play a poorly understood but important role in motor control. Striatal-associated behavioral ( Carbon et al, 2011 ) and functional imaging abnormalities are present in primary dystonia (reviewed in Pappas et al (2014) ), and altering basal ganglia output with deep brain stimulation therapy is an effective dystonia treatment ( Vidailhet et al, 2013 ). Despite this evidence, the key striatal cell type(s) that drive dystonic movements are unknown.…”

Section: Introductionmentioning

confidence: 99%

Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons

Pappas

Darr

Holley

et al. 2015

eLife

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Striatal dysfunction plays an important role in dystonia, but the striatal cell types that contribute to abnormal movements are poorly defined. We demonstrate that conditional deletion of the DYT1 dystonia protein torsinA in embryonic progenitors of forebrain cholinergic and GABAergic neurons causes dystonic-like twisting movements that emerge during juvenile CNS maturation. The onset of these movements coincides with selective degeneration of dorsal striatal large cholinergic interneurons (LCI), and surviving LCI exhibit morphological, electrophysiological, and connectivity abnormalities. Consistent with the importance of this LCI pathology, murine dystonic-like movements are reduced significantly with an antimuscarinic agent used clinically, and we identify cholinergic abnormalities in postmortem striatal tissue from DYT1 dystonia patients. These findings demonstrate that dorsal LCI have a unique requirement for torsinA function during striatal maturation, and link abnormalities of these cells to dystonic-like movements in an overtly symptomatic animal model.DOI: http://dx.doi.org/10.7554/eLife.08352.001

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Mouse Models of Neurodevelopmental Disease of the Basal Ganglia and Associated Circuits

Cited by 35 publications

References 421 publications

The DYT6 Dystonia Protein THAP1 Regulates Myelination within the Oligodendrocyte Lineage

The DYT6 Dystonia Protein THAP1 Regulates Myelination within the Oligodendrocyte Lineage

Centella asiatica increases hippocampal synaptic density and improves memory and executive function in aged mice

Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons

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