The fast-spiking parvalbumin (PV) interneurons play a critical role in neural circuit activity and dysfunction of these cells has been implicated in the cognitive deficits typically observed in schizophrenia patients. Due to the high metabolic demands of PV neurons, they are particularly susceptible to oxidative stress. Given the extant literature exploring the pathological effects of oxidative stress on PV cells in cortical regions linked to schizophrenia, we decided to investigate whether PV neurons in other select brain regions, including sub-cortical structures, may be differentially affected by redox dysregulation induced oxidative stress during neurodevelopment in mice with a genetically compromised glutathione synthesis (Gclm KO mice).
View Article and Find Full Text PDFThe adult dentate gyrus produces new neurons that morphologically and functionally integrate into the hippocampal network. In the adult brain, most excitatory synapses are ensheathed by astrocytic perisynaptic processes that regulate synaptic structure and function. However, these processes are formed during embryonic or early postnatal development and it is unknown whether astrocytes can also ensheathe synapses of neurons born during adulthood and, if so, whether they play a role in their synaptic transmission.
View Article and Find Full Text PDFIn Alzheimer's disease (AD), synaptic alterations play a major role and are often correlated with cognitive changes. In order to better understand synaptic modifications, we compared alterations in NMDA receptors and postsynaptic protein PSD-95 expression in the entorhinal cortex (EC) and frontal cortex (FC; area 9) of AD and control brains. We combined immunohistochemical and image analysis methods to quantify on consecutive sections the distribution of PSD-95 and NMDA receptors GluN1, GluN2A and GluN2B in EC and FC from 25 AD and control cases.
View Article and Find Full Text PDFTwenty patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) meeting the EFNS/PNS criteria were examined in order to assess differences/similarities between the various grading systems according to CIDP disease activity status (CDAS). A principal component (PC) analysis and the correlations between the following scores were performed: Neurological Symptom Score; MRC sum score; Neurological Impairment Score; Hammersmith Functional Motor Scale; Inflammatory Neuropathy Cause and Treatment (INCAT) Sensory Sum Score; Overall Disability Sum Score; INCAT Disability Score; Rasch-built Overall Disability Scale. Our analysis outlined two main sets of scales, with high influence in the top two PCs.
View Article and Find Full Text PDFA hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks. The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress. Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.
View Article and Find Full Text PDFIn the present work we studied synaptic protein concentrations in relation to behavioral performance. Long-Evans rats, aged 22-23 months, were classified for individual expression of place memory in the Morris water maze, in reference to young adults. Two main subgroups of aged rats were established: the Aged cognitively Unimpaired (AU) had search accuracy within the range (percent of time in training sector within mean ± 2 SEM) of young rats and the Aged cognitively Impaired (AI) rats had search accuracy below this range.
View Article and Find Full Text PDFBackground: A hallmark of the pathophysiology of schizophrenia is a dysfunction of parvalbumin-expressing fast-spiking interneurons, which are essential for the coordination of neuronal synchrony during sensory and cognitive processing. Oxidative stress as observed in schizophrenia affects parvalbumin interneurons. However, it is unknown whether the deleterious effect of oxidative stress is particularly prevalent during specific developmental time windows.
View Article and Find Full Text PDFLimiting the development of secondary damage represents one of the major goals of neuroprotective therapies after spinal cord injury. Here, we demonstrate that specific JNK inhibition via a single intraperitoneal injection of the cell permeable peptide D-JNKI1 6h after lesion improves locomotor recovery assessed by both the footprint and the BMS tests up to 4 months post-injury in mice. JNK inhibition prevents c-jun phosphorylation and caspase-3 cleavage, has neuroprotective effects and results in an increased sparing of white matter at the lesion site.
View Article and Find Full Text PDFIn mice, barrels in layer IV of the somatosensory cortex correspond to the columnar representations of whisker follicles. In barrelless (BRL) mice, barrels are absent, but functionally, a columnar organization persists. Previously we characterized the aberrant geometry of thalamic projection of BRL mice using axonal reconstructions of individual neurons.
View Article and Find Full Text PDFMyotonic dystrophy type 1 (DM1) is a multisystem disorder with a variable phenotype. The involvement of peripheral nerves in DM1 disease is controversial. The DM1 animal model DM300 transgenic mice that carry 350 to 500 CTG repeats express a mild DM1 phenotype but do not exhibit motor or sensory pathology.
View Article and Find Full Text PDFGenetic studies have shown an association between schizophrenia and a GAG trinucleotide repeat (TNR) polymorphism in the catalytic subunit (GCLC) of the glutamate cysteine ligase (GCL), the key enzyme for glutathione (GSH) synthesis. The present study was aimed at analyzing the influence of a GSH dysregulation of genetic origin on plasma thiols (total cysteine, homocysteine, and cysteine-glycine) and other free amino acid levels as well as fibroblast cultures GSH levels. Plasma thiols levels were also compared between patients and controls.
View Article and Find Full Text PDFElevated oxidative stress and alteration in antioxidant systems, including glutathione (GSH) decrease, are observed in schizophrenia. Genetic and functional data indicate that impaired GSH synthesis represents a susceptibility factor for the disorder. Here, we show that a genetically compromised GSH synthesis affects the morphological and functional integrity of hippocampal parvalbumin-immunoreactive (PV-IR) interneurons, known to be affected in schizophrenia.
View Article and Find Full Text PDFActa Neurobiol Exp (Wars)
March 2010
GABA receptors are ubiquitous in the cerebral cortex and play a major role in shaping responses of cortical neurons. GABA(A) and GABA(B) receptor subunit expression was visualized by immunohistochemistry in human auditory areas from both hemispheres in 9 normal subjects (aged 43-85 years; time between death and fixation 6-24 hours) and in 4 stroke patients (aged 59-87 years; time between death and fixation 7-24 hours) and analyzed qualitatively for GABA(A) and semiquantitatively for GABA(B) receptor subunits. In normal brains, the primary auditory area (TC) and the surrounding areas TB and TA displayed distinct GABA(A) receptor subunit labeling with differences among cortical layers and areas.
View Article and Find Full Text PDFPresenilin 1 (PS1) mutations are responsible for a majority of early onset familial Alzheimer's disease (FAD) cases, in part by increasing the production of Abeta peptides. However, emerging evidence suggests other possible effects of PS1 on synaptic dysfunction where PS1 might contribute to the pathology independent of Abeta. We chose to study the L286V mutation, an aggressive FAD mutation which has never been analyzed at the electrophysiological and morphological levels.
View Article and Find Full Text PDFIn order to understand relationships between executive and structural deficits in the frontal cortex of patients within normal aging or Alzheimer's disease, we studied frontal pathological changes in young and old controls compared to cases with sporadic (AD) or familial Alzheimer's disease (FAD). We performed a semi-automatic computer assisted analysis of the distribution of beta-amyloid (Abeta) deposits revealed by Abeta immunostaining as well as of neurofibrillary tangles (NFT) revealed by Gallyas silver staining in Brodman areas 10 (frontal polar), 12 (ventro-infero-median) and 24 (anterior cingular), using tissue samples from 5 FAD, 6 sporadic AD and 10 control brains. We also performed densitometric measurements of glial fibrillary acidic protein, principal compound of intermediate filaments of astrocytes, and of phosphorylated neurofilament H and M epitopes in areas 10 and 24.
View Article and Find Full Text PDFAccumulating evidence supports a role for brain-derived neurotrophic factor (BDNF) in depression. However, most of these studies have been performed in animal models that have a low face validity with regard to the human disease. Here, we examined the regulation of BDNF expression in the hippocampus and amygdala of rats subjected to the chronic mild stress (CMS) model of depression, a paradigm that induces anhedonia, a core symptom of depression.
View Article and Find Full Text PDFThe physical disector is a method of choice for estimating unbiased neuron numbers; nevertheless, calibration is needed to evaluate each counting method. The validity of this method can be assessed by comparing the estimated cell number with the true number determined by a direct counting method in serial sections. We reconstructed a 1/5 of rat lumbar dorsal root ganglia taken from two experimental conditions.
View Article and Find Full Text PDFWe investigated how synaptic plasticity is related to the neurodegeneration process in the human dorsolateral prefrontal cortex. Pre- and postsynaptic proteins of Brodmann's area 9 from patients with Alzheimer's disease (AD) and age-matched controls were quantified by immunohistochemical methods and Western blots. The main finding was a significant increase in the expression of postsynaptic density protein PSD-95 in AD brains, revealed on both sections and immunoblots, while the expression of spinophilin, associated to spines, remained quantitatively unchanged despite qualitative changes with age and disease.
View Article and Find Full Text PDFMyotonic dystrophy Type 1 (DM-1) is caused by abnormal expansion of a (CTG) repeat located in the DM protein kinase gene. Respiratory problems have long been recognized to be a major feature of this disorder. Because respiratory failure can be associated with dysfunction of phrenic nerves and diaphragm muscle, we examined the diaphragm and respiratory neural network in transgenic mice carrying the human genomic DM-1 region with expanded repeats of more than 300 CTG, a valid model of the human disease.
View Article and Find Full Text PDFIn order to understand how plasticity is related to neurodegeneration, we studied synaptic proteins with quantitative immunohistochemistry in the entorhinal cortex from Alzheimer patients and age-matched controls. We observed a significant decrease in presynaptic synaptophysin and an increase in postsynaptic density protein PSD-95, positively correlated with beta amyloid and phosphorylated Tau proteins in Alzheimer cases. Furthermore, Alzheimer-like neuritic retraction was generated in okadaic acid (OA) treated SH-SY5Y neuroblastoma cells with no decrease in PSD-95 expression.
View Article and Find Full Text PDFSynthesis of glutathione, a major redox regulator, is compromised in schizophrenia. We postulated that the resulting glutathione deficit via its effect on redox-sensitive proteins could contribute to dysfunction of some neurotransmitter systems in schizophrenia. We investigated whether a glutathione deficit, induced by a blocker of glutathione synthesis, L-buthionine-(S,R)-sulfoximine, affects intracellular pathways implicated in dopamine signaling in neurons, namely dopamine modulation of calcium responses to NMDA.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
October 2007
Schizophrenia is a complex multifactorial brain disorder with a genetic component. Convergent evidence has implicated oxidative stress and glutathione (GSH) deficits in the pathogenesis of this disease. The aim of the present study was to test whether schizophrenia is associated with a deficit of GSH synthesis.
View Article and Find Full Text PDFBackground: Neurosphere-derived cells (NC), containing neural stem cells, various progenitors and more differentiated cells, were obtained from newborn C57/BL6 mice and infused in a murine model of focal ischemia with reperfusion to investigate if: 1) they decreased ischemic injury and restored brain function; 2) they induced changes in the environment in which they are infused; 3) changes in brain environment consequent to transient ischemia were relevant for NC action.
Methodology/principal Findings: NC were infused intracerebroventricularly 4 h or 7 d after 30 min middle cerebral artery occlusion. In ischemic mice receiving cells at 4 h, impairment of open field performance was significantly improved and neuronal loss significantly reduced 7-14 d after ischemia compared to controls and to ischemic mice receiving cells at 7 d.
It has been already demonstrated that thyroid hormone (T3) is one of the most important stimulating factors in peripheral nerve regeneration. We have recently shown that local administration of T3 in silicon tubes at the level of the transected rat sciatic nerve enhanced axonal regeneration and improved functional recovery. Silicon, however, cannot be used in humans because it causes a chronic inflammatory reaction.
View Article and Find Full Text PDFImmunocompetent microglia play an important role in the pathogenesis of Alzheimer's disease (AD). Antimicroglial antibodies in the cerebrospinal fluid (CSF) in clinically diagnosed AD patients have been previously recorded. Here, we report the results of the analysis of the CSF from 38 autopsy cases: 7 with definite AD; 14 with mild and 10 with moderate Alzheimer's type pathology; and 7 controls.
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