Maturation of "neocortex isole" in vivo in mice.

How much neocortical development depends on connections remains elusive. Here, we show that Celsr3|Dlx mutant mice have no extrinsic neocortical connections yet survive to postnatal day 20, acquire a basic behavioral repertoire, and display spontaneous hyperactivity, with abnormal light/dark activity cycling. Except for hallmarks related to thalamic input, such as barrels in somatosensory cortex, cortical arealization and laminar maturation proceeded normally. However, the tangential extension of the mature cortex was diminished, with radial thickness less severely affected. Deep layer neurons were reduced in number, and their apical and basal dendritic arbors were blunted, with reduced synapse density. Interneurons reached the cortex, and their density was comparable with wild type. The excitability of mutant pyramidal neurons, measured in vitro in patch-clamp experiments in acute slices, was decreased. However, their firing activity in vivo was quite similar to the wild type, except for the presence of rapid firing exhaustion in some mutant neurons. Local field potential and electrocorticogram showed similar range of oscillations, albeit with higher frequency peaks and reduced left-right synchrony in the mutant. Thus, "protomap" formation, namely cortical lamination and arealization, proceed normally in absence of extrinsic connections, but survival of projection neurons and acquisition of mature morphological and some electrophysiological features depend on the establishment of normal cortical-subcortical relationships.

Central Sleep Apnea Syndrome Can Complicate Neuromyelitis Optica Spectrum Disorder: A Case Report.

Neuromyelitis optica spectrum disorder is a rare, relapsing autoimmune disease of the central nervous system. Various initial presentations can delay diagnosis and treatment. A 14-year-old girl was admitted to the emergency department owing to respiratory insufficiency. Repeated history-taking and neuroimaging revealed an area postrema syndrome. A diagnosis of neuromyelitis optica spectrum disorder with positive aquaporin-4 antibodies has finally been established. The patient improved significantly with immunosuppressive therapy. However, her 3-year follow-up still showed sleep-disordered breathing requiring nocturnal bilevel positive airway pressure therapy. We report an original case of NMOSD leading to persistent central sleep apnea syndrome.

Purkinje cell BKchannel ablation induces abnormal rhythm in deep cerebellar nuclei and prevents LTD.

Purkinje cells (PC) control deep cerebellar nuclei (DCN), which in turn inhibit inferior olive nucleus, closing a positive feedback loop via climbing fibers. PC highly express potassium BK channels but their contribution to the olivo-cerebellar loop is not clear. Using multiple-unit recordings in alert mice we found in that selective deletion of BK channels in PC induces a decrease in their simple spike firing with a beta-range bursting pattern and fast intraburst frequency (~200 Hz). To determine the impact of this abnormal rhythm on the olivo-cerebellar loop we analyzed simultaneous rhythmicity in different cerebellar structures. We found that this abnormal PC rhythmicity is transmitted to DCN neurons with no effect on their mean firing frequency. Long term depression at the parallel-PC synapses was altered and the intra-burst complex spike spikelets frequency was increased without modification of the mean complex spike frequency in BK-PC-/- mice. We argue that the ataxia present in these conditional knockout mice could be explained by rhythmic disruptions transmitted from mutant PC to DCN but not by rate code modification only. This suggests a neuronal mechanism for ataxia with possible implications for human disease.

Downregulation of the Glial GLT1 Glutamate Transporter and Purkinje Cell Dysfunction in a Mouse Model of Myotonic Dystrophy.

Brain function is compromised in myotonic dystrophy type 1 (DM1), but the underlying mechanisms are not fully understood. To gain insight into the cellular and molecular pathways primarily affected, we studied a mouse model of DM1 and brains of adult patients. We found pronounced RNA toxicity in the Bergmann glia of the cerebellum, in association with abnormal Purkinje cell firing and fine motor incoordination in DM1 mice. A global proteomics approach revealed downregulation of the GLT1 glutamate transporter in DM1 mice and human patients, which we found to be the result of MBNL1 inactivation. GLT1 downregulation in DM1 astrocytes increases glutamate neurotoxicity and is detrimental to neurons. Finally, we demonstrated that the upregulation of GLT1 corrected Purkinje cell firing and motor incoordination in DM1 mice. Our findings show that glial defects are critical in DM1 brain pathophysiology and open promising therapeutic perspectives through the modulation of glutamate levels.

Anti-GQ1b antibody syndrome presenting as acute isolated bilateral ophthalmoplegia: Report on two patients and review of the literature.

BACKGROUND: Miller Fisher syndrome (MFS) is an acute polyradiculoneuritis regarded as an uncommon clinical variant of Guillain-Barré syndrome (GBS). MFS is characterized by the acute onset of the clinical triad of ophthalmoplegia, cereballar ataxia and areflexia. Atypical forms of MFS presenting as isolated ophthalmoplegia without ataxia have been rarely described, mostly in adults. PATIENTS: We present two cases of acute isolated bilateral ophthalmoplegia in childhood, both occurring shortly after Campylobacter jejuni enteritis. Serum analysis of anti-ganglioside antibodies revealed elevated levels of anti-GQ1b IgG and IgM. We observed in both children complete spontaneous resolution several weeks after onset. CONCLUSION: The cases of the two patients confirm the rare but possible occurrence of atypical MFS in young children a few weeks after gastrointestinal infection. Identification of high levels of anti-GQ1b antibodies in the serum may help confirm the diagnosis of MFS even when its clinical presentation is incomplete.

RFT1-congenital disorder of glycosylation (CDG) syndrome: a cause of early-onset severe epilepsy.

RFT1-congenital disorder of glycosylation (CDG) syndrome, a recessive N-glycosylation disorder caused by mutation in the RFT1 gene, is a very rare subtype of CDG syndrome associated with deafness, developmental delay, and non-specific epilepsy. The aim of this report is to describe the electroclinical presentation of epilepsy associated with this condition. [Published with video sequences online].

Regulatory role of host CD8+ T lymphocytes in experimental graft-versus-host disease across a single major histocompatibility complex class II incompatibility.

BACKGROUND: CD8+ T cells are known to regulate type 2 helper T cell (Th2) alloreactive immune responses but their mode of activation is unclear. We investigated the role of host CD8+ T cells in experimental Th2-type graft-versus-host disease (GVHD) where donor/recipient disparity is restricted to a single major histocompatibility complex (MHC) class II antigen. METHODS: Immunoglobulin (Ig) E serum levels, eosinophilia and lymphoid tissue hyperplasia were compared after injection of bm12 CD4+ T cells in either wild-type or CD8+ T cell-deficient (CD8-/-) C57BL/6 mice. In vitro, we explored effects of the addition of CD8+ T cells from wild-type or IFN-gamma-/- mice in mixed leukocyte cultures prepared with beta2 microglobulin-deficient (beta2m-/-) CD4+ T cells as responders or beta2m dendritic cells as stimulators. RESULTS: HyperIgE resolved after 3 weeks in wild-type hosts whereas it persisted for 6 weeks in CD8-/- hosts. Eosinophil infiltrates in lymph nodes were significantly enhanced in CD8-/- hosts. Increased serum levels of IL-5 and IL-13 in CD8-/- hosts confirmed the enhancement of Th2-type responses in the context of recipient CD8+ T cell deficiency. Hyperplasia of lymph nodes and spleen were similar in both groups, as well as in vivo proliferation of donor CD4+ T cells. In vitro, CD8+ T cell regulation of the alloreactive Th2 response depended on their production of IFN-gamma and did not require expression of beta2m on CD4+ T cells or antigen-presenting cells. CONCLUSIONS: Host CD8+ T cells regulate alloreactive Th2 responses during graft-versus-host disease through an IFN-gamma dependent pathway, independently of the recognition of beta2m-associated MHC class I molecules.

Protein tyrosine phosphatase receptor type R is required for Purkinje cell responsiveness in cerebellar long-term depression.

BACKGROUND: Regulation of synaptic connectivity, including long-term depression (LTD), allows proper tuning of cellular signalling processes within brain circuitry. In the cerebellum, a key centre for motor coordination, a positive feedback loop that includes mitogen-activated protein kinases (MAPKs) is required for proper temporal control of LTD at cerebellar Purkinje cell synapses. Here we report that the tyrosine-specific MAPK-phosphatase PTPRR plays a role in coordinating the activity of this regulatory loop. RESULTS: LTD in the cerebellum of Ptprr (-/-) mice is strongly impeded, in vitro and in vivo. Comparison of basal phospho-MAPK levels between wild-type and PTPRR deficient cerebellar slices revealed increased levels in mutants. This high basal phospho-MAPK level attenuated further increases in phospho-MAPK during chemical induction of LTD, essentially disrupting the positive feedback loop and preventing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) phosphorylation and endocytosis. CONCLUSIONS: Our findings indicate an important role for PTPRR in maintaining low basal MAPK activity in Purkinje cells. This creates an optimal 'window' to boost MAPK activity following signals that induce LTD, which can then propagate through feed-forward signals to cause AMPAR internalization and LTD.

Novel LMNA mutation presenting as severe congenital muscular dystrophy.

Mutations in the lamin A/C gene determine a heterogeneous group of congenital diseases, termed laminopathies, consisting of more than 15 phenotypes, including autosomal dominant Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy type 1B. Early onset in infancy has been described in these muscular dystrophies. Reported here is a 7-year-old male with congenital muscular dystrophy. Remarkably, muscle weakness and wasting affected predominantly axial muscles as well as proximal upper and distal lower extremities. The patient rapidly developed joint contractures and spine rigidity with the head only mildly flexed. Serum creatine kinase was moderately elevated. Muscle biopsy indicated a dystrophic pattern with normal immunochemical findings. A novel, de novo missense substitution p.Asn39Tyr within the lamin A/C gene confirmed the diagnosis of a laminopathy. This report broadens the spectrum of lamin A/C gene mutations and illustrates the phenotypic variability of laminopathies with early onset congenital muscular dystrophy. Mutations in the lamin A/C gene should be sought in any infant with dystrophic features and normal tissue immunochemical studies; especially in the presence of moderately elevated serum creatine kinase, predominant axial and humeroperoneal weakness, spine rigidity, and joint contractures.