Quantitative cellular changes in multiple system atrophy brains.

Multiple system atrophy (MSA) is a neurodegenerative disorder characterised by a combined symptomatology of parkinsonism, cerebellar ataxia, autonomic failure and corticospinal dysfunction. In brains of MSA patients, the hallmark lesion is the aggregation of misfolded alpha-synuclein in oligodendrocytes. Even though the underlying pathological mechanisms remain poorly understood, the evidence suggests that alpha-synuclein aggregation in oligodendrocytes may contribute to the neurodegeneration seen in MSA. The primary aim of this review is to summarise the published stereological data on the total number of neurons and glial cell subtypes (oligodendrocytes, astrocytes and microglia) and volumes in brains from MSA patients. Thus, we include in this review exclusively the reports of unbiased quantitative data from brain regions including the neocortex, nuclei of the cerebrum, the brainstem and the cerebellum. Furthermore, we compare and discuss the stereological results in the context of imaging findings and MSA symptomatology. In general, the stereological results agree with the common neuropathological findings of neurodegeneration and gliosis in brains from MSA patients and support a major loss of nigrostriatal neurons in MSA patients with predominant parkinsonism (MSA-P), as well as olivopontocerebellar atrophy in MSA patients with predominant cerebellar ataxia (MSA-C). Surprisingly, the reports indicate only a minor loss of oligodendrocytes in sub-cortical regions of the cerebrum (glial cells not studied in the cerebellum) and negligible changes in brain volumes. In the past decades, the use of stereological methods has provided a vast amount of accurate information on cell numbers and volumes in the brains of MSA patients. Combining different techniques such as stereology and diagnostic imaging (e.g. MRI, PET and SPECT) with clinical data allows for a more detailed interdisciplinary understanding of the disease and illuminates the relationship between neuropathological changes and MSA symptomatology.

Quantitative Cellular Changes in the Thalamus of Patients with Multiple System Atrophy.

The thalamus is a brain region consisting of anatomical and functional connections between various spinal, subcortical, and cortical regions, which has a putative role in the clinical manifestation of Multiple System Atrophy (MSA). Previous stereological studies have reported significant anatomical alterations in diverse brain regions of MSA patients, including the cerebral cortex, basal ganglia and white matter, but no quantitative studies have examined the thalamus. To establish the extent of thalamic involvement, we applied stereological methods to estimate the total number of neurons and glial cells (oligodendrocytes, astrocytes and microglia) as well as the volume in two thalamic sub-regions, the mediodorsal nucleus (MDT) and the anterior principal nucleus (APn), in brains from ten MSA patients and 11 healthy control subjects. Compared to healthy controls, MSA patients had significantly fewer neurons (26%) in the MDT, but not the APn. We also found significantly more astrocytes (32%) and microglia (54%) in the MDT, with no such changes in the APn. Finally, we saw no group differences in the total number of oligodendrocytes. Our findings show a region-specific loss of thalamic neurons that occurs without loss of oligodendrocytes, whereas thalamic microgliosis seems to occur alongside astrogliosis. These pathological changes in the thalamus may contribute to the cognitive impairment seen in most patients with MSA.

Is There a Correlation Between the Number of Brain Cells and IQ?

Our access to a unique material of postmortem brains obtained from decades of data collection enabled a stereological analysis of the neuron numbers and correlation of results with individual premorbid intelligence quotient (IQ) data. In our sample of 50 brains from men, we find that IQ does not correlate with the number of brain cells in the human neocortex and was only weakly correlated to brain weight. Our stereological examination extended to measures of several other parameters that might be of relevance to intelligence, including numbers of cerebral glial cells (astrocytes, oligodendrocytes, and microglia) and the volume of key areas in the gray and white matter and of the cerebral ventricles, also showing near-zero nonsignificant correlations to IQ.

Pathological changes in the cerebellum of patients with multiple system atrophy and Parkinson's disease-a stereological study.

Multiple system atrophy (MSA) and Parkinson's disease (PD) are synucleinopathies characterized by aggregation of α-synuclein in brain cells. Recent studies have shown that morphological changes in terms of cerebral nerve cell loss and increase in glia cell numbers, the degree of brain atrophy and molecular and epidemiological findings are more severe in MSA than PD. In the present study, we performed a stereological comparison of cerebellar volumes, granule and Purkinje cells in 13 patients diagnosed with MSA [8 MSA-P (striatonigral subtype) and 5 MSA-C (olivopontocerebellar subtype)], 12 PD patients, and 15 age-matched control subjects. Only brains from MSA-C patients showed a reduction in the total number of Purkinje cells (anterior lobe) whereas both MSA-P and MSA-C patients had reduced Purkinje cell volumes (perikaryons and nuclei volume). The cerebellum of both diseases showed a reduction in the white matter volume compared to controls. The number of granule cells was unaffected in both diseases. Analyses of cell type-specific mRNA expression supported our structural data. This study of the cerebellum is in line with previous findings in the cerebrum and demonstrates that the degree of morphological changes is more pronounced in MSA-C than MSA-P and PD. Further, our results support an explicit involvement of cerebellar Purkinje cells and white matter connectivity in MSA-C > MSA-P and points to the potential importance of white matter alterations in PD pathology.

Electroconvulsive treatment prevents chronic restraint stress-induced atrophy of the hippocampal formation-A stereological study.

INTRODUCTION: Electroconvulsive therapy (ECT) is one of the most efficient treatments of major depressive disorder (MDD), although the underlying neurobiology remains poorly understood. There is evidence that ECT and MDD exert opposing effects on the hippocampal formation with respect to volume and number of neurons. However, there has been a paucity of quantitative data in experimental models of ECT and MDD. METHODS: Using design-based stereology, we have measured the effects of a stress-induced depression model (chronic restraint stress, CRS) and ECS on the morphology of the hippocampus by estimating the volume and total number of neurons in the hilus, CA1, and CA2/3, as well as in the entire hippocampus. RESULTS: We find that CRS induces a significant decrease in volume exclusively of the hilus and that ECS (CRS + ECS) blocks this reduction. Furthermore, ECS alone does not change the volume or total number of neurons in the entire hippocampus or any hippocampal subdivision in our rat model.

Electroconvulsive stimulation, but not chronic restraint stress, causes structural alterations in adult rat hippocampus--a stereological study.

The neurobiological mechanisms underlying depression are not fully understood. Only a few previous studies have used validated stereological methods to test how stress and animal paradigms of depression affect adult hippocampal neurogenesis and whether antidepressant therapy can counteract possible changes in an animal model. Thus, in this study we applied methods that are state of the art in regard to stereological cell counting methods. Using a validated rat model of depression in combination with a clinically relevant schedule of electroconvulsive stimulation, we estimated the total number of newly formed neurons in the hippocampal subgranular zone. Also estimated were the total number of neurons and the volume of the granule cell layer in adult rats subjected to chronic restraint stress and electroconvulsive stimulation either alone or in combination. We found that chronic restraint stress induces depression-like behavior, without significantly changing neurogenesis, the total number of neurons or the volume of the hippocampus. Further, electroconvulsive stimulation prevents stress-induced depression-like behavior and increases neurogenesis. The total number of neurons and the granule cell layer volume was not affected by electroconvulsive stimulation.

Methamphetamine-induced changes in the mice hippocampal neuropeptide Y system: implications for memory impairment.

Methamphetamine (METH) is a psychostimulant drug that causes irreversible brain damage leading to several neurological and psychiatric abnormalities, including cognitive deficits. Neuropeptide Y (NPY) is abundant in the mammalian central nervous system (CNS) and has several important functions, being involved in learning and memory processing. It has been demonstrated that METH induces significant alteration in mice striatal NPY, Y(1) and Y(2) receptor mRNA levels. However, the impact of this drug on the hippocampal NPY system and its consequences remain unknown. Thus, in this study, we investigated the effect of METH intoxication on mouse hippocampal NPY levels, NPY receptors function, and memory performance. Results show that METH increased NPY, Y(2) and Y(5) receptor mRNA levels, as well as total NPY binding accounted by opposite up- and down-regulation of Y(2) and Y(1) functional binding, respectively. Moreover, METH-induced impairment in memory performance and AKT/mammalian target of rapamycin pathway were both prevented by the Y(2) receptor antagonist, BIIE0246. These findings demonstrate that METH interferes with the hippocampal NPY system, which seems to be associated with memory failure. Overall, we concluded that Y(2) receptors are involved in memory deficits induced by METH intoxication.

Combined gene overexpression of neuropeptide Y and its receptor Y5 in the hippocampus suppresses seizures.

We recently demonstrated that recombinant adeno-associated viral vector-induced hippocampal overexpression of neuropeptide Y receptor, Y2, exerts a seizure-suppressant effect in kindling and kainate-induced models of epilepsy in rats. Interestingly, additional overexpression of neuropeptide Y in the hippocampus strengthened the seizure-suppressant effect of transgene Y2 receptors. Here we show for the first time that another neuropeptide Y receptor, Y5, can also be overexpressed in the hippocampus. However, unlike Y2 receptor overexpression, transgene Y5 receptors in the hippocampus had no effect on kainate-induced motor seizures in rats. However, combined overexpression of Y5 receptors and neuropeptide Y exerted prominent suppression of seizures. This seizure-suppressant effect of combination gene therapy with Y5 receptors and neuropeptide Y was significantly stronger as compared to neuropeptide Y overexpression alone. These results suggest that overexpression of Y5 receptors in combination with neuropeptide Y could be an alternative approach for more effective suppression of hippocampal seizures.

Adeno-associated viral vector-induced overexpression of neuropeptide Y Y2 receptors in the hippocampus suppresses seizures.

Gene therapy using recombinant adeno-associated viral vectors overexpressing neuropeptide Y in the hippocampus exerts seizure-suppressant effects in rodent epilepsy models and is currently considered for clinical application in patients with intractable mesial temporal lobe epilepsy. Seizure suppression by neuropeptide Y in the hippocampus is predominantly mediated by Y2 receptors, which, together with neuropeptide Y, are upregulated after seizures as a compensatory mechanism. To explore whether such upregulation could prevent seizures, we overexpressed Y2 receptors in the hippocampus using recombinant adeno-associated viral vectors. In two temporal lobe epilepsy models, electrical kindling and kainate-induced seizures, vector-based transduction of Y2 receptor complementary DNA in the hippocampus of adult rats exerted seizure-suppressant effects. Simultaneous overexpression of Y2 and neuropeptide Y had a more pronounced seizure-suppressant effect. These results demonstrate that overexpression of Y2 receptors (alone or in combination with neuropeptide Y) could be an alternative strategy for epilepsy treatment.

Involvement of Y(5) receptors in neuropeptide Y agonist-induced analgesic-like effect in the rat hot plate test.

Neuropeptide Y (NPY) induces analgesic-like effects after central administration across diverse pain models in rodents. In spinal pain models, previous studies indicate a prominent role for Y(1) receptors at mediating this effect of NPY. In supraspinal pain models like the hot plate test, the NPY receptors involved have not been thoroughly explored. By intracerebroventricular (i.c.v.) administration of selective NPY receptor ligands, the possible involvement of Y(5) receptors in analgesic-like mechanisms was investigated using the hot plate test in rats. Both NPY and selective Y(5) agonists induced analgesic-like effects as revealed by prolonged hot plate latencies. Further consistent with a role for Y(5) receptors, pretreatment with a selective Y(5) receptor antagonist blocked the Y(5) agonist-induced analgesic-like effect. The present study indicates involvement of Y(5) receptors probably at the supraspinal level in mediation of NPY agonist-induced analgesic-like effects in the hot plate test.