Neurobiology of disease
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Neurobiology of disease · Feb 2011
BDNF and TrkB in neuronal differentiation of Fmr1-knockout mouse.
Fragile X syndrome (FXS) is a common cause of inherited mental retardation and the best characterized form of autistic spectrum disorders. FXS is caused by the loss of functional fragile X mental retardation protein (FMRP), which leads to abnormalities in the differentiation of neural progenitor cells (NPCs) and in the development of dendritic spines and neuronal circuits. Brain-derived neurotrophic factor (BDNF) and its TrkB receptors play a central role in neuronal maturation and plasticity. ⋯ Pilocarpine-induced seizures caused an accumulation of Bdnf mRNA transcripts in the most proximal segments of dendrites in cortical but not in hippocampal neurons of Fmr1-KO mice. In addition, BDNF protein levels were increased in the hippocampus but reduced in the cortex of Fmr1-KO mice in line with regional differences of synaptic plasticity in the brain of Fmr1-KO mice. Altogether, the present data suggest that alterations in the BDNF/TrkB signaling modulate brain development and impair synaptic plasticity in FXS.
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Neurobiology of disease · Feb 2011
Lack of dystrophin functionally affects α3β2/β4-nicotinic acethylcholine receptors in sympathetic neurons of dystrophic mdx mice.
In the sympathetic superior cervical ganglion (SCG), nicotinic acetylcholine receptors (nAChRs) mediate fast synaptic transmission. We previously demonstrated that in SCG neurons of mdx mice, an animal model for Duchenne muscular dystrophy, lack of dystrophin causes a decrease, compared to the wild-type, in post-synaptic nAChRs containing the α3 subunit associated with β2 and/or β4 (α3β2/β4-nAChRs), but not in those containing the α7 subunit. ⋯ This reduction associates with that of protein levels of α3, β2 and β4 subunits. Therefore, we suggest that, in mdx mouse SCG neurons, lack of dystrophin, by specifically affecting membrane stabilization of α3β2/β4-nAChRs, could determine an increase in receptor internalization and degradation, with consequent reduction in the fast intraganglionic cholinergic transmission.
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Neurobiology of disease · Feb 2011
Monocarboxylate transporter 1 is deficient on microvessels in the human epileptogenic hippocampus.
Monocarboxylate transporter 1 (MCT1) facilitates the transport of important metabolic fuels (lactate, pyruvate and ketone bodies) and possibly also acidic drugs such as valproic acid across the blood-brain barrier. Because an impaired brain energy metabolism and resistance to antiepileptic drugs are common features of temporal lobe epilepsy (TLE), we sought to study the expression of MCT1 in the brain of patients with this disease. Immunohistochemistry and immunogold electron microscopy were used to assess the distribution of MCT1 in brain specimens from patients with TLE and concomitant hippocampal sclerosis (referred to as mesial TLE or MTLE (n=15)), patients with TLE and no hippocampal sclerosis (non-MTLE, n=13) and neurologically normal autopsy subjects (n=8). ⋯ Patients with MTLE were markedly deficient in MCT1 on microvessels in several areas of the hippocampal formation, especially CA1, which exhibited a 37% to 48% loss of MCT1 on the plasma membrane of endothelial cells when compared with non-MTLE. These findings suggest that the uptake of blood-derived monocarboxylate fuels and possibly also acidic drugs, such as valproic acid, is perturbed in the epileptogenic hippocampus, particularly in MTLE. We hypothesize that the loss of MCT1 on brain microvessels is mechanistically involved in the pathophysiology of drug-resistant TLE, and propose that re-expression of MCT1 may represent a novel therapeutic approach for this disease.
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Neurobiology of disease · Feb 2011
Comparative StudyMigraine preventive drugs differentially affect cortical spreading depression in rat.
Cortical spreading depression (CSD) is the most likely cause of the migraine aura. Drugs with distinct pharmacological properties are effective in the preventive treatment of migraine. To test the hypothesis that their common denominator might be suppression of CSD we studied in rats the effect of three drugs used in migraine prevention: lamotrigine which is selectively effective on the aura but not on the headache, valproate and riboflavin which have a non-selective effect. ⋯ Lamotrigine has a marked suppressive effect which correlates with its rather selective action on the migraine aura. Valproate and riboflavin have no effect on the triggering of CSD, although they are effective in migraine without aura. Taken together, these results are compatible with a causal role of CSD in migraine with aura, but not in migraine without aura.
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Neurobiology of disease · Feb 2011
NF-κB in the mechanism of brain edema in acute liver failure: studies in transgenic mice.
Astrocyte swelling and brain edema are major complications of the acute form of hepatic encephalopathy (acute liver failure, ALF). While elevated brain ammonia level is a well-known etiological factor in ALF, the mechanism by which ammonia brings about astrocyte swelling is not well understood. We recently found that astrocyte cultures exposed to ammonia activated nuclear factor-κB (NF-κB), and that pharmacological inhibition of such activation led to a reduction in astrocyte swelling. ⋯ By contrast, ammonia significantly increased cell swelling (31.7%) in cultured astrocytes from WT mice and displayed cytological abnormalities. Moreover, we observed a lesser increment in iNOS and NADPH oxidase activity (the latter is also known to be activated by NF-κB and to contribute to astrocyte swelling) in astrocyte cultures from Tg mice treated with ammonia, as compared to ammonia-treated WT mice astrocytes. These findings strongly suggest that activation of NF-κB is a critical factor in the development of astrocyte swelling/brain edema in ALF.