Elevated P75NTR expression causes death of engrailed-deficient midbrain dopaminergic neurons by Erk1/2 suppression

<p>Abstract</p> <p>Background</p> <p>The homeodomain transcription factors <it>Engrailed-1 </it>and <it>Engrailed-2 </it>are required for the survival of mesencephalic dopaminergic (mesDA) neurons in a cell-autonomous and gene-dose-dependent manner. Homozygote mutant mice, deficient of both genes (<it>En1-/-;En2-/-</it>), die at birth and exhibit a loss of all mesDA neurons by mid-gestation. In heterozygote animals (<it>En1+/-;En2-/-</it>), which are viable and fertile, postnatal maintenance of the nigrostriatal dopaminergic system is afflicted, leading to a progressive degeneration specific to this subpopulation and Parkinson's disease-like molecular and behavioral deficits.</p> <p>Results</p> <p>In this work, we show that the dose of <it>Engrailed </it>is inversely correlated to the expression level of the pan-neurotrophin receptor gene <it>P75</it>^{<it>NTR </it>}(<it>Ngfr</it>). Loss of mesDA neurons in the <it>Engrailed</it>-null mutant embryos is caused by elevated expression of this neurotrophin receptor: Unusually, in this case, the cell death signal of P75^NTRis mediated by suppression of Erk1/2 (extracellular-signal-regulated kinase 1/2) activity. The reduction in expression of <it>Engrailed</it>, possibly related to the higher levels of P75^NTR, also decreases mitochondrial stability. In particular, the dose of <it>Engrailed </it>determines the sensitivity to cell death induced by the classic Parkinson-model toxin MPTP and to inhibition of the anti-apoptotic members of the Bcl-2 family of proteins.</p> <p>Conclusion</p> <p>Our study links the survival function of the <it>Engrailed </it>genes in developing mesDA neurons to the regulation of <it>P75</it>^{<it>NTR </it>}and the sensitivity of these neurons to mitochondrial insult. The similarities to the disease etiology in combination with the nigral phenotype of <it>En1+/-;En2-/- </it>mice suggests that haplotype variations in the <it>Engrailed </it>genes and/or <it>P75</it>^{<it>NTR </it>}that alter their expression levels could, in part, determine susceptibility to Parkinson's disease.</p

Embryonic Exposure to Valproic Acid Affects Social Predispositions for Dynamic Cues of Animate Motion in Newly-Hatched Chicks

Early predispositions to preferentially orient towards cues associated with social partners have been documented in several vertebrate species including human neonates and domestic chicks. Human newborns at high familiar risk of Autism Spectrum Disorder (ASD) show differences in their attention toward these predisposed stimuli, suggesting potential impairments in these social-orienting mechanisms in ASD. Using embryonic exposure to valproic acid (VPA) we modelled ASD behavioural deficits in domestic chicks. To investigate social predispositions towards animate motion in domestic chicks, we focused on self-propulsion, using two video-animations representing a simple red circle moving at constant speed (speed-constant) or one that was changing its speed (accelerating and decelerating; speed-change). Using a six minutes spontaneous choice test for the two stimuli, we compared unlearned preferences for stimuli that autonomously change speed between VPA- and vehicle-injected chicks. We found that the preference for speed changes was abolished in VPA-injected chicks compared to vehicle-injected controls. These results add to previous findings indicating similar impairments for static social stimuli and suggest a specific effect of VPA on the development of mechanisms that enhance orienting towards animate stimuli. These findings strengthen the hypothesis of an early impairment of predispositions in the early development of ASD. Hence, early predispositions are a potentially useful tool to detect early ASD symptoms in human neonates and to investigate the molecular and neurobiological mechanisms underlying the onset of this neurodevelopmental disorder

Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants.

Gamma-aminobutyric acid (GABA) and glutamate are the most abundant amino acid neurotransmitters in the brain. GABA, an inhibitory neurotransmitter, is synthesized by glutamic acid decarboxylase (GAD). Its predominant isoform GAD67, contributes up to ∼90% of base-level GABA in the CNS, and is encoded by the GAD1 gene. Disruption of GAD1 results in an imbalance of inhibitory and excitatory neurotransmitters, and as Gad1-/- mice die neonatally of severe cleft palate, it has not been possible to determine any potential neurological dysfunction. Furthermore, little is known about the consequence of GAD1 disruption in humans. Here we present six affected individuals from six unrelated families, carrying bi-allelic GAD1 variants, presenting with developmental and epileptic encephalopathy, characterized by early-infantile onset epilepsy and hypotonia with additional variable non-CNS manifestations such as skeletal abnormalities, dysmorphic features and cleft palate. Our findings highlight an important role for GAD1 in seizure induction, neuronal and extraneuronal development, and introduce GAD1 as a new gene associated with developmental and epileptic encephalopathy

Characterization of the Engrailed mutant mice as experimental models for Parkinson's disease

Engrailed genes are homeodomain-containing transcription factors necessary for the development and maintenance of mesencephalic dopaminergic neurons. Deletion in the Engrailed genes has been shown to affect the survival of mesencephalic dopaminergic neurons both during development and in the adult. Here we describe for the first time a significant reduction in striatal dopamine levels in En1+/-;En2+/- mice compared with their En2+/- littermates, accompanied by a modest reduction in the number of nigral DA neurons. Our results strengthen previous evidence indicating Engrailed genes as survival factors for mature dopaminergic neurons. Furthermore, our data suggest a role for these transcription factors in the maintenance of synaptic dopaminergic neurotransmission in adult neuron

Fetal blockade of nicotinic acetylcholine transmission causes autism-like impairment of biological motion preference in the neonatal chick

Several environmental chemicals are suspected risk factors for autism spectrum disorder (ASD), including valproic acid (VPA) and pesticides acting on nicotinic acetylcholine receptors (nAChRs), if administered during pregnancy. However, their target processes in fetal neuro-development are unknown. We report that the injection of VPA into the fetus impaired imprinting to an artificial object in neonatal chicks, while a predisposed preference for biological motion (BM) remained intact. Blockade of nAChRs acted oppositely, sparing imprinting and impairing BM preference. Beside ketamine and tubocurarine, significant effects of imidacloprid (a neonicotinoid insecticide) appeared at a dose ≤1 ppm. In accord with the behavioral dissociations, VPA enhanced histone acetylation in the primary cell culture of fetal telencephalon, whereas ketamine did not. VPA reduced the brain weight and the ratio of NeuN-positive cells (matured neurons) in the telencephalon of hatchlings, whereas ketamine/tubocurarine did not. Despite the distinct underlying mechanisms, both VPA and nAChR blockade similarly impaired imprinting to biological image composed of point-light animations. Furthermore, both impairments were abolished by postnatal bumetanide treatment, suggesting a common pathology underlying the social attachment malformation. Neurotransmission via nAChR is thus critical for the early social bond formation, which is hindered by ambient neonicotinoids through impaired visual predispositions for animate objects