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Huntington’s disease (HD) is characterised by specific degeneration of striatal GABAergic medium spiny neurons (MSNs) occurs. Implementation of cell replacement strategies for HD using pluripotent stem cells (PSC) requires development and characterisation of new differentiation protocols since the available protocols are too long and inefficient. This can be partially explained because striatal developmental biology is quiet unknown and based on rodent developmental studies. Our present aim is to establish specific human gene expression profile that can be used for the refinement of MSN differentiation protocols. In this view, we analyse quantitative expression of 112 genes involved in telencephalon development, subpallium specification and striatal maturation in human fetal and adult tissues. We also compare post-mortem caudate and putamen nuclei of control and HD patients in order to establish differential expression gene pattern to be used as baseline in in vitro disease models. Unbiased hierarchical cluster analysis reveals human whole ganglionic eminence (WGE) specific gene expression profile compared to fetal cortex and to adult striatal nuclei. Further analysis show a specific developmental pattern of expression in those genes involved in striatal specification. Expression levels comparison of control human tissues against diseased samples suggests specific pathways impairment. In conclusion, we present a new quantitative dataset which spread new light on human striatal nucleus development at gene expression level. Interestingly, this dataset can be used as a baseline to evaluate the efficiency of available and future differentiation protocols helping refinement and evaluating the effects of modifications when improving. Furthermore, this approach may identify gene expression profiles that reflect HD-specific phenotypes.

Huntington’s disease (HD) is a hereditary neurodegenerative disorder characterised by motor disturbances and cognitive impairment, the latter being increasingly associated to hippocampal dysfunction. Brain derived neurotrophic factor (BDNF) is a potent neurotrophin that modulates hippocampal synaptic plasticity through its receptors TrkB and p75NTR. Fingolimod (FTY720), an agonist of sphingosine-1 phosphate receptors currently used to treat Multiple Sclerosis, has recently been shown to increase BDNF levels. We have investigated the potential beneficial effects of FTY720 in treating synaptic and memory impairments in a R6/1 HD mouse model. FTY720 delivery promoted BDNF synthesis, but not pro-BDNF cleavage, in the R6/1 hippocampus. Chronic administration of FTY720 rescued long-term memory deficits in R6/1 mice and increased the number of dendritic spines in the CA1 area of the hippocampus. R6/1 mice displayed an imbalance of p75NTR/TrkB in the hippocampus, which was prevented by FTY720 treatment through negative modulation of p75NTR. As a result, R6/1 mice showed reduced RhoA activity and higher activation of TrkB and CREB, supporting the role of FTY720 in the enhancement of synaptic plasticity. Our findings define a new mechanism for the action of FTY720 in neurodegenerative diseases, and propose this drug as a suitable candidate for treating cognitive dysfunction in HD.

Huntington’s disease (HD) is a fatal neurodegenerative disease caused by an expanded CAG trinucleotide repeat in the gene encoding the protein huntingtin, it presents with abnormal motor coordination, cognitive decline and psychiatric disorders; the pathophysiology includes reduced levels of brain-derived neurotrophic factor (BDNF) in the brain; thus BDNF activation through its high-affinity receptor TrkB has become of interest for its therapeutic implications. 7,8-Dihydroxyflavone (7,8-DHF) has been described as a robust TrkB receptor agonist in a whole variety of in vitro models and tested on in vivo models of neurodegenerative diseases. Previously it has been described that chronic treatment with 7,8 DHF can ameliorate motor deficits in N171-82Q HD mice; here we tested its effects on cognitive and motor deficits on the R6/1 mouse model of HD. We found chronic treatment with 7,8 DHF is able to delay the onset of motor deficits in R6/1 mice assessed by the Rotarod test; furthermore 7,8 DHF reversed the inability to perform correctly the Novel Object Recognition Test (NORT) at 15 weeks; pathological and biochemical analyses of treated mice revealed improved levels of Enkephalin in striatum, (concordant with a trend on a DARPP32 recovery) and a reduction of striatal volume loss upon treatment. Interestingly in vivo results showed a TrkB Y816 but not TrkB Y515 phosphorylation recovery in striatum with acute and chronic treatment. 7,8 DHF treatment in primary neuronal cultures revealed the same differences in TrkB phosphorylation profile (selective phosphorylation of Y816 residues) and morphologic divergent changes from controls with BDNF. Our results suggest 7,8 DHF has therapeutic potential for HD but also that 7,8 DHF has differential effects from BDNF that should be further investigated.