ABSTRACT
OBJECTIVE: To show that immunotherapy with medications such mycophenolate mofetil (MMF) can cause serious complications in patients with neuromuscular disorders. METHODS: Two patients with neuromuscular disorders on immunotherapy with long-term MMF who developed toxoplasmic encephalitis (TE) were included in this case series. RESULTS: One patient with myasthenia gravis and one patient with inflammatory myopathy on immunotherapy with long-term MMF developed severe TE. Diagnosis was based on clinical presentation, MRI brain imaging characteristics, and CSF PCR positivity for Toxoplasma gondii. Both patients were treated with pyrimethamine, sulfadiazine, and leucovorin for 2 months without clinical improvement, and both died. CONCLUSIONS: Immunotherapy with medications such as MMF can cause devastating TE in non-HIV patients with neuromuscular disorders. Early consideration and recognition of this complication is important to possibly prevent unfavorable outcomes. The utility of screening and prophylaxis against toxoplasmosis in individuals with neuroimmunologic disorders and other autoimmune disorders who receive immunosuppressive therapy requires future study.
ABSTRACT
NR3A is the only NMDA receptor (NMDAR) subunit that downregulates sharply prior to the onset of sensitive periods for plasticity, yet the functional importance of this transient expression remains unknown. To investigate whether removal/replacement of juvenile NR3A-containing NMDARs is involved in experience-driven synapse maturation, we used a reversible transgenic system that prolonged NR3A expression in the forebrain. We found that removal of NR3A is required to develop strong NMDAR currents, full expression of long-term synaptic plasticity, a mature synaptic organization characterized by more synapses and larger postsynaptic densities, and the ability to form long-term memories. Deficits associated with prolonged NR3A were reversible, as late-onset suppression of transgene expression rescued both synaptic and memory impairments. Our results suggest that NR3A behaves as a molecular brake to prevent the premature strengthening and stabilization of excitatory synapses and that NR3A removal might thereby initiate critical stages of synapse maturation during early postnatal neural development.
Subject(s)
Down-Regulation/physiology , Memory/physiology , Neurons/cytology , Receptors, N-Methyl-D-Aspartate/metabolism , Synapses/physiology , Animals , Animals, Newborn , Biophysics , Disks Large Homolog 4 Protein , Electric Stimulation/methods , Food Preferences/physiology , Green Fluorescent Proteins/genetics , Guanylate Kinases , Hippocampus/cytology , Immunoprecipitation/methods , In Vitro Techniques , Intracellular Signaling Peptides and Proteins/metabolism , Maze Learning/physiology , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microscopy, Electron, Transmission/methods , Neuronal Plasticity/genetics , Neuronal Plasticity/physiology , Neurons/ultrastructure , Patch-Clamp Techniques/methods , Receptors, N-Methyl-D-Aspartate/genetics , Recognition, Psychology/physiology , Silver Staining/methods , Social Behavior , Synaptic Potentials/genetics , Synaptic Potentials/physiologyABSTRACT
Experience-dependent maturation of neocortical circuits is required for normal sensory and cognitive abilities, which are distorted in neurodevelopmental disorders. We tested whether experience-dependent neocortical modifications require Ube3a, an E3 ubiquitin ligase whose dysregulation has been implicated in autism and Angelman syndrome. Using visual cortex as a model, we found that experience-dependent maturation of excitatory cortical circuits was severely impaired in Angelman syndrome model mice deficient in Ube3a. This developmental defect was associated with profound impairments in neocortical plasticity. Normal plasticity was preserved under conditions of sensory deprivation, but was rapidly lost by sensory experiences. The loss of neocortical plasticity is reversible, as late-onset visual deprivation restored normal synaptic plasticity. Furthermore, Ube3a-deficient mice lacked ocular dominance plasticity in vivo when challenged with monocular deprivation. We conclude that Ube3a is necessary for maintaining plasticity during experience-dependent neocortical development and suggest that the loss of neocortical plasticity contributes to deficits associated with Angelman syndrome.
