Retinoic acid receptor beta protects striatopallidal medium spiny neurons from mitochondrial dysfunction and neurodegeneration.

Retinoic acid is a powerful regulator of brain development, however its postnatal functions only start to be elucidated. We show that retinoic acid receptor beta (RARß), is involved in neuroprotection of striatopallidal medium spiny neurons (spMSNs), the cell type affected in different neuropsychiatric disorders and particularly prone to degenerate in Huntington disease (HD). Accordingly, the number of spMSNs was reduced in the striatum of adult Rarß-/- mice, which may result from mitochondrial dysfunction and neurodegeneration. Mitochondria morphology was abnormal in mutant mice whereas in cultured striatal Rarß-/- neurons mitochondria displayed exacerbated depolarization, and fragmentation followed by cell death in response to glutamate or thapsigargin-induced calcium increase. In vivo, Rarß-/- spMSNs were also more vulnerable to the mitochondrial toxin 3-nitropropionic acid (3NP), known to induce HD symptoms in human and rodents. In contrary, an RARß agonist, AC261066, decreased glutamate-induced toxicity in primary striatal neurons in vitro, and diminished mitochondrial dysfunction, spMSN cell death and motor deficits induced in wild type mice by 3NP. We demonstrate that the striatopallidal pathway is compromised in Rarß-/- mice and associated with HD-like motor abnormalities. Importantly, similar motor abnormalities and selective reduction of spMSNs were induced by striatal or spMSN-specific inactivation of RARß, further supporting a neuroprotective role of RARß in postnatal striatum.

Raman Imaging Reveals Accumulation of Hemoproteins in Plaques from Alzheimer's Diseased Tissues.

Hemes have been suggested to play a central role in Alzheimer's disease since they show high peroxidase reactivity when bound to amyloid ß peptides, leading to the production of reactive oxygen species. Here we used Fourier transform infrared and Raman imaging on Alzheimer's diseased mice and human brain tissue. Our finding suggests the accumulation of hemes in the senile plaques of both murine and human samples. We compared the Raman signature of the plaques to the ones of various hemeoproteins and to the hemin-Aß-42 complex. The detected Raman signature of the plaques does not allow identifying the type of heme accumulating in the plaques.

Retinoic Acid Receptor ß Controls Development of Striatonigral Projection Neurons through FGF-Dependent and Meis1-Dependent Mechanisms.

The mammalian striatum controls sensorimotor and psychoaffective functions through coordinated activities of its two striatonigral and striatopallidal output pathways. Here we show that retinoic acid receptor ß (RARß) controls development of a subpopulation of GABAergic, Gad65-positive striatonigral projection neurons. In Rarb(-/-) knock-out mice, concomitant reduction of Gad65, dopamine receptor D1 (Drd1), and substance P expression at different phases of prenatal development was associated with reduced number of Drd1-positive cells at birth, in contrast to normal numbers of striatopallidal projection neurons expressing dopamine receptor D2. Fate mapping using BrdU pulse-chase experiments revealed that such deficits may originate from compromised proliferation of late-born striosomal neurons and lead to decreased number of Drd1-positive cells retaining BrdU in postnatal day (P) 0 Rarb(-/-) striatum. Reduced expression of Fgf3 in the subventricular zone of the lateral ganglionic eminence (LGE) at embryonic day 13.5 may underlie such deficits by inducing premature differentiation of neuronal progenitors, as illustrated by reduced expression of the proneural gene Ascl1 (Mash1) and increased expression of Meis1, a marker of postmitotic LGE neurons. In agreement with a critical role of FGF3 in this control, reduced number of Ascl1-expressing neural progenitors, and a concomitant increase of Meis1-expressing cells, were observed in primary cell cultures of Rarb(-/-) LGE. This defect was normalized by addition of fibroblast growth factor (FGF). Such data point to role of Meis1 in striatal development, also supported by reduced neuronal differentiation in the LGE of Meis1(-/-) embryos. Our data unveil a novel mechanism of development of striatonigral projection neurons involving retinoic acid and FGF, two signals required for positioning the boundaries of Meis1-expressing cells.

Retinoic acid regulates olfactory progenitor cell fate and differentiation.

BACKGROUND: In order to fulfill their chemosensory function, olfactory neurons are in direct contact with the external environment and are therefore exposed to environmental aggressive factors. Olfaction is maintained through life because, unlike for other sensory neuroepithelia, olfactory neurons have a unique capacity to regenerate after trauma. The mechanisms that control the ontogenesis and regenerative ability of these neurons are not fully understood. Here, we used various experimental approaches in two model systems (chick and mouse) to assess the contribution of retinoic acid signaling in the induction of the olfactory epithelium, the generation and maintenance of progenitor populations, and the ontogenesis and differentiation of olfactory neurons. RESULTS: We show that retinoic acid signaling, although dispensable for initial induction of the olfactory placode, plays a key role in neurogenesis within this neuroepithelium. Retinoic acid depletion in the olfactory epithelium, both in chick and mouse models, results in a failure of progenitor cell maintenance and, consequently, differentiation of olfactory neurons is not sustained. Using an explant system, we further show that renewal of olfactory neurons is hindered if the olfactory epithelium is unable to synthesize retinoic acid. CONCLUSIONS: Our data show that retinoic acid is not a simple placodal inductive signal, but rather controls olfactory neuronal production by regulating the fate of olfactory progenitor cells. Retinaldehyde dehydrogenase 3 (RALDH3) is the key enzyme required to generate retinoic acid within the olfactory epithelium.