Loss of Wdfy3 in mice alters cerebral cortical neurogenesis reflecting aspects of the autism pathology.

Autism spectrum disorders (ASDs) are complex and heterogeneous developmental disabilities affecting an ever-increasing number of children worldwide. The diverse manifestations and complex, largely genetic aetiology of ASDs pose a major challenge to the identification of unifying neuropathological features. Here we describe the neurodevelopmental defects in mice that carry deleterious alleles of the Wdfy3 gene, recently recognized as causative in ASDs. Loss of Wdfy3 leads to a regionally enlarged cerebral cortex resembling early brain overgrowth described in many children on the autism spectrum. In addition, affected mouse mutants display migration defects of cortical projection neurons, a recognized cause of epilepsy, which is significantly comorbid with autism. Our analysis of affected mouse mutants defines an important role for Wdfy3 in regulating neural progenitor divisions and neural migration in the developing brain. Furthermore, Wdfy3 is essential for cerebral expansion and functional organization while its loss-of-function results in pathological changes characteristic of ASDs

A TSPO ligand is protective in a mouse model of multiple sclerosis.

Local production of neurosteroids such as progesterone and allopregnanolone confers neuroprotection in central nervous system (CNS) inflammatory diseases. The mitochondrial translocator protein (TSPO) performs a rate-limiting step in the conversion of cholesterol to pregnenolone and its steroid derivatives. Previous studies have shown that TSPO is upregulated in microglia and astroglia during neural inflammation, and radiolabelled TSPO ligands such as PK11195 have been used to image and localize injury in the CNS. Recent studies have shown that modulating TSPO activity with pharmacological ligands such as etifoxine can initiate the production of neurosteroids locally in the injured CNS. In this study, we examined the effects of etifoxine, a clinically available anxiolytic drug, in the development and progression of mouse experimental autoimmune encephalomyelitis (EAE), an experimental model for multiple sclerosis (MS). Our results showed that etifoxine attenuated EAE severity when administered before the development of clinical signs and also improved symptomatic recovery when administered at the peak of the disease. In both cases, recovery was correlated with diminished inflammatory pathology in the lumbar spinal cord. Modulation of TSPO activity by etifoxine led to less peripheral immune cell infiltration of the spinal cord, and increased oligodendroglial regeneration after inflammatory demyelination in EAE. Our results suggest that a TSPO ligand, e.g. etifoxine, could be a potential new therapeutic option for MS with benefits that could be comparable to the administration of systemic steroids but potentially avoiding the detrimental side effects of long-term direct use of steroids

Author Correction: Role of astroglia in Down's syndrome revealed by patient-derived human-induced pluripotent stem cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

c- and N-myc Regulate Neural Precursor Cell Fate, Cell Cycle, and Metabolism to Direct Cerebellar Development

Separate murine knockout (KO) of either c- or N-myc genes in neural stem and precursor cells (NSC) driven by nestin-cre causes microcephaly. The cerebellum is particularly affected in the N-myc KO, leading to a strong reduction in cerebellar granule neural progenitors (CGNP) and mature granule neurons. In humans, mutation of N-myc also causes microcephaly in Feingold Syndrome. We created a double KO (DKO) of c- and N-myc using nestin-cre, which strongly impairs brain growth, particularly that of the cerebellum. Granule neurons were almost absent from the Myc DKO cerebellum, and other cell types were relatively overrepresented, including astroglia, oligodendrocytes, and Purkinje neurons. These findings are indicative of a profound disruption of cell fate of cerebellar stem and precursors. DKO Purkinje neurons were strikingly lacking in normal arborization. Inhibitory neurons were ectopic and exhibited very abnormal GAD67 staining patterns. Also consistent with altered cell fate, the adult DKO cerebellum still retained a residual external germinal layer (EGL). CGNP in the DKO EGL were almost uniformly NeuN and p27KIP1 positive as well as negative for Math1 and BrdU at the peak of normal cerebellar proliferation at P6. The presence of some mitotic CGNP in the absence of S phase cells suggests a possible arrest in M phase. CGNP and NSC metabolism also was affected by loss of Myc as DKO cells exhibited weak nucleolin staining. Together these findings indicate that c- and N-Myc direct cerebellar development by maintaining CGNP and NSC populations through inhibiting differentiation as well as directing rapid cell cycling and active cellular metabolism

Arthrogryposis: A Review and Update

ongenital contractures can be divided into two groups: isolated contractures and multiple contractures (Fig. 1). Isolated congenital contractures affect only a single area of the body; the most common isolated contracture is congenital clubfoot, which occurs in one of every 500 live births1. The term arthrogryposis is often used as shorthand to de-scribe multiple congenital contractures that affect two or more different areas of the body. Arthrogryposis is not a specific di-agnosis, but rather a clinical finding, and it is a characteristic of more than 300 different disorders2,3. The overall prevalence of arthrogryposis is one in 3000 live births4. The inheritance, natural history, treatment guidelines, and outcomes of arthro-gryposis vary among disorders, underscoring the importance of making a specific diagnosis in each child1,5-10. The purpose of thi

The vulnerability of thalamocortical circuitry to hypoxic-ischemic injury in a mouse model of periventricular leukomalacia.

BackgroundPeriventricular leukomalacia (PVL) is the leading cause of neurological disabilities including motor and cognitive deficits in premature infants. Periventricular leukomalacia is characterized by damage to the white matter in the immature brain, but the mechanisms by which damage to immature white matter results in widespread deficits of cognitive and motor function are unclear. The thalamocortical system is crucial for human consciousness and cognitive functions, and impaired development of the cortico-thalamic projections in the neonatal period is implicated to contribute importantly to abnormalities of cognitive function in children with PVL.ResultsIn this study, using a mouse model of PVL, we sought to test the hypothesis that PVL-like injury affects the different components of the thalamocortical circuitry that can be defined by vesicular glutamate transporters 1 and 2 (vGluT1 and vGluT2), both of which are required for glutamatergic synaptic transmission in the central nervous system. We combined immunocytochemistry and immuno-electron microscopy to investigate changes in cortico-thalamic synapses which were specifically identified by vGluT1 immunolabeling. We found that a drastic reduction in the density of vGluT1 labeled profiles in the somatosensory thalamus, with a reduction of 72-74 % in ventroposterior (VP) nucleus and a reduction of 42-82 % in thalamic reticular nucleus (RTN) in the ipsilateral side of PVL mice. We further examined these terminals at the electron microscopic level and revealed onefold-twofold decrease in the sizes of vGluT1 labeled corticothalamic terminals in VP and RTN. The present study provides anatomical and ultrastructural evidence to elucidate the cellular mechanisms underlying alteration of thalamic circuitry in a mouse model of PVL, and reveals that PVL-like injury has a direct impact on the corticothalamic projection system.ConclusionsOur findings provide the first set of evidence showing that the thalamocortical circuitry is affected and vulnerable in PVL mice, supporting a working model in which vGluT1 defined corticothalamic synapses are altered in PVL mice, and vGluT2 defined thalamocortical synapses are associated with such changes, leading to the compromised thalamocortical circuitry in the PVL mice. Our study demonstrates that the thalamocortical circuitry is highly vulnerable to hypoxia-ischemia in the PVL model, thus identifying a novel target site in PVL pathology