Astrocytes, an active player in Aicardi-Goutières syndrome.

Aicardi-Goutières syndrome (AGS) is an early-onset, autoimmune and genetically heterogeneous disorder with severe neurologic injury. Molecular studies have established that autosomal recessive mutations in one of the following genes are causative: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1 and IFIH1/MDA5. The phenotypic presentation and pathophysiology of AGS is associated with over-production of the cytokine Interferon-alpha (IFN-α) and its downstream signaling, characterized as type I interferonopathy. Astrocytes are one of the major source of IFN in the central nervous system (CNS) and it is proposed that they could be key players in AGS pathology. Astrocytes are the most ubiquitous glial cell in the CNS and perform a number of crucial and complex functions ranging from formation of blood-brain barrier, maintaining ionic homeostasis, metabolic support to synapse formation and elimination in healthy CNS. Involvement of astrocytic dysfunction in neurological diseases-Alexander's disease, Epilepsy, Alzheimer's and amyotrophic lateral sclerosis (ALS)-has been well-established. It is now known that compromised astrocytic function can contribute to CNS abnormalities and severe neurodegeneration, nevertheless, its contribution in AGS is unclear. The current review discusses known molecular and cellular pathways for AGS mutations and how it stimulates IFN-α signaling. We shed light on how astrocytes might be key players in the phenotypic presentations of AGS and emphasize the cell-autonomous and non-cell-autonomous role of astrocytes. Understanding the contribution of astrocytes will help reveal mechanisms underlying interferonopathy and develop targeted astrocyte specific therapeutic treatments in AGS.

Reduction of serotonergic neurons in the dorsal raphe due to chronic prenatal administration of a tryptophan-free diet.

Serotonin (5-HT) is a widely studied neurotransmitter which plays an important role in the development and proper functioning of the organism throughout life. The appearance of 5-HT system early in ontogeny suggests the hypothesis that 5-HT plays a regulatory role in neurodevelopment. This study investigated the effect of administration of a tryptophan deficient diet during prenatal development on the morphology and cell population of the dorsal raphe. The experimental diet, containing balanced amounts of carbohydrates, lipids and proteins, was provided to a time-mated group of rats from gestational day 5 until delivery. Control groups were fed with (i) the experimental diet formulation with 0.2% tryptophan added to the mixture, or (ii) a regular chow diet. At delivery, five pups per dam were euthanized. Body and brain weight was measured and brain sections were processed for immunohistochemistry for tryptophan hydroxylase (TrpH) and whole brain 5-HT analysis. Sections containing dorsal raphe were photographed with a light microscope and TrpH positive neurons quantified. Brain weights in the tryptophan deprived group showed no difference as compared with controls while body weights were reduced by 25%. Total numbers of serotonergic neurons at the dorsal raphe in the prenatal tryptophan deficient pups were reduced by 35%. A regional analysis of the dorsal raphe indicated a marked cellular reduction in the medial and caudal sections of the nucleus, which contains the majority of serotonergic neurons, in the tryptophan deprived condition. Quantitative 5-HT analysis showed that the brain concentration was similar among conditions. In conclusion, gestational tryptophan deprivation exerts adverse effects on the development of the 5-HT system, particularly in the dorsal raphe, manifested by decreased numbers of serotonergic neurons as well as altered topography in this important nucleus.

Thyroid hormone receptor beta mutation causes severe impairment of cerebellar development.

Cerebellar development on the postnatal period is mainly characterized by cellular proliferation in the external granular layer (EGL) followed by migration of granular cells in the molecular layer through the Bergmann glia (BG) fibers in order to form the granular layer in the adult. All these events are drastically affected by thyroid hormones (TH), which actions are mainly mediated by alpha (TRalpha) and beta (TRbeta) nuclear receptor isoforms. Here, we analyzed the effects of a natural human mutation (337T) in the TRbeta locus, which impairs T3 binding to its receptor, on the mouse cerebellum ontogenesis. We report that target inactivation of TRbeta-TH binding leads to a smaller cerebellum area characterized by impaired lamination and foliation. Further, TRbeta mutant mice presented severe deficits in proliferation of granular precursors, arborization of Purkinje cells and organization of BG fibers. Together, our data suggest that the action of TH via TRbeta regulates important events of cerebellar ontogenesis contributing to a better understanding of some neuroendocrine disorders. Further, our data correlate TRbeta with cerebellar foliation, and provide, for the first time, evidence of a receptor-mediated mechanism underlying TH actions on this event.

Loss of neuronal projections in the dystrophin-deficient mdx mouse is not progressive.

Lack of dystrophin is known to reduce several cerebral fiber systems. To investigate if the loss of fibers is progressive, we analyzed projections of the trigeminal sensory system to the red nucleus in 3, 6, and 12 month old dystrophin-deficient mdx mice. The retrograde tracer fluorogold was injected in the magnocellular part of the red nucleus, and the number of labeled neurons in the oral part of the spinal trigeminal nucleus (Sp5O) was counted. We found that the number of labeled Sp5O neurons was reduced by 50% in mdx mice compared to age-matched control mice. The number of labeled Sp5O neurons did not change significantly between 3 and 12 months neither in mdx nor in control mice. In addition, the number of labeled neurons in the interstitial system of the trigeminal nerve was reduced by 43% in mdx mice. We conclude that fiber loss did not continue beyond the age of 3 months. Our data suggest that lack of full-length dystrophin impairs neuronal migration or axonal outgrowth, or increases neuronal death during fetal or early life.

Disruption of cortical development as a consequence of repetitive pilocarpine-induced status epilepticus in rats.

PURPOSE: The aim of the present study was to observe possible cortical abnormalities after repetitive pilocarpine-induced status epilepticus (SE) in rats during development. METHODS: Wistar rats received intraperitoneal injection of pilocarpine hydrochloride 2% (380 mg/kg) at P7, P8, and P9. All experimental rats displayed SE after pilocarpine injections. Rats were killed at P10 and P35, and immunocytochemistry procedures were performed on 50-microm vibratome sections, by using antibodies against nonphosphorylated neurofilament (SMI-311), parvalbumin (PV), calbindin (CB), calretinin (CR), and glutamate decarboxylase (GAD-65). Selected sections were used for the TUNEL method and double-labeling experiments, with different mixtures of the same markers. RESULTS: The major findings of the present work were (a) altered intracortical circuitry development; (b) anticipation of PV immunoreactivity in neocortical interneurons; (c) increased GAD-65 immunoreactivity; and (d) reduced neocortical apoptotic process. CONCLUSIONS: From these results, we suggest that previously healthy brain, without genetic abnormalities, might develop an "acquired" disruption of cortical development whose evolution reproduces some characteristics of the childhood epilepsies associated with cognitive impairment.

[In utero macrocephaly as clinical manifestation of glutaric aciduria type I. Report of a novel mutation]. / Macrocefalia in utero como manifestación clínica de aciduria glutárica tipo I. Informe de una nueva mutacion.

INTRODUCTION: Macrocephaly is a pivotal clinical sign, associated with multiple neurological diseases, particularly neurometabolical ones, such as the glutaric aciduria type I (GA I). This aciduria resulting from the genetical deficiency of the enzyme glutaryl-CoA dehydrogenase (GCDH). Is a relatively common cause of acute metabolic brain damage in early childhood. We report on one case of GA I, with early manifestations since fetal period and a novel mutation. CASE REPORT: Our patient was referred due macrocephaly in utero and occipitofrontal head circumference above the 98 percentile for chronologic age during first few months of life, hypotonia and development delay. The metabolic investigations of organic acids in urine and acylcarnitine profile in blood, the brain magnetic resonance and the molecular analyses of the glutaryl-CoA deshidrogenase gene, confirm the diagnosis. The molecular analysis allowed to identify one previously described mutation A293T and a novel mutation IVS5-2 A>G. CONCLUSION: It is important the recognition of in utero macrocephaly as a sign to early diagnosis of glutaric aciduria type I to initiate specific therapy to prevent the encephalopathic crises and minimize brain damage in patients who are already neurologically impaired.