Decreased Dendritic Spine Density on Prefrontal Cortical Pyramidal Neurons in Schizophrenia

Glantz, Leisa A.; Lewis, David A.

doi:10.1001/archpsyc.57.1.65

Cited by 1,440 publications

(1,105 citation statements)

References 75 publications

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“…Metabolic systems are strongly linked to the control of synaptic protein connectivity, signaling, and turnover (41-45). Thus, decreases in mitochondrial function coupled with abnormal glucose utilization in neurons could reduce the capacity of pyramidal cells to sustain a normal complement of dendritic spines, contributing to the lower DLPFC spine density reported in schizophrenia (38, 46, 47). …”

Section: Discussionmentioning

confidence: 99%

Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

et al. 2018

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Schizophrenia is a devastating illness that affects over 2 million people in the U.S. and costs society billions of dollars annually. New insights into the pathophysiology of schizophrenia are needed to provide the conceptual framework to facilitate development of new treatment strategies. We examined bioenergetic pathways in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia and control subjects using western blot analysis, quantitative real-time polymerase chain reaction, and enzyme/substrate assays. Laser-capture microdissection-qPCR was used to examine these pathways at the cellular level. We found decreases in hexokinase (HXK) and phosphofructokinase (PFK) activity in the DLPFC, as well as decreased PFK1 mRNA expression. In pyramidal neurons, we found an increase in monocarboxylate transporter 1 mRNA expression, and decreases in HXK1, PFK1, glucose transporter 1 (GLUT1), and GLUT3 mRNA expression. These results suggest abnormal bioenergetic function, as well as a neuron-specific defect in glucose utilization, in the DLPFC in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

et al. 2018

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“…It has been reported that the prefrontal cortex of subjects with SZ contains fewer dendritic spines. 67 Improper folding of actin or other functional related molecules, indirectly influenced by TCP1, may contribute to the cytoskeleton deficit in multiple brain areas in SZ postmortem samples.…”

Section: Synapse and Neurotransmissionmentioning

confidence: 99%

An integrated genomic analysis of gene-function correlation on schizophrenia susceptibility genes

Chu

Liu

2010

J Hum Genet

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Schizophrenia is a highly complex inheritable disease characterized by numerous genetic susceptibility elements, each contributing a modest increase in risk for the disease. Although numerous linkage or association studies have identified a large set of schizophrenia-associated loci, many are controversial. In addition, only a small portion of these loci overlaps with the large cumulative pool of genes that have shown changes of expression in schizophrenia. Here, we applied a genomic gene-function approach to identify susceptibility loci that show direct effect on gene expression, leading to functional abnormalities in schizophrenia. We carried out an integrated analysis by cross-examination of the literature-based susceptibility loci with the schizophrenia-associated expression gene list obtained from our previous microarray study (Journal of Human Genetics (2009) 54: 665-75) using bioinformatic tools, followed by confirmation of gene expression changes using qPCR. We found nine genes (CHGB, SLC18A2, SLC25A27, ESD, C4A/C4B, TCP1, CHL1 and CTNNA2) demonstrate gene-function correlation involving: synapse and neurotransmission; energy metabolism and defense mechanisms; and molecular chaperone and cytoskeleton. Our findings further support the roles of these genes in genetic influence and functional consequences on the development of schizophrenia. It is interesting to note that four of the nine genes are located on chromosome 6, suggesting a special chromosomal vulnerability in schizophrenia.

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“…Indeed, in the last few decades, multiple lines of evidence have shown that disruptions in dendritic spine shape, size, or number invariably accompany various brains disorders, such as schizophrenia [6][7][8][9], Angelman syndrome [10], and Rett syndrome [11][12][13], and may be even be a characteristic feature of traumatic brain injuries [14,15]. What do these various neuropsychiatric and neurodevelopmental diseases share in common?…”

Section: Introductionmentioning

confidence: 99%

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

Lefort

2015

Neurotherapeutics

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Alzheimer's disease (AD) is a monumental public health crisis with no effective cure or treatment. To date, therapeutic strategies have focused almost exclusively on upstream signaling events in the disease, namely on β-amyloid and amyloid precursor protein processing, and have, unfortunately, yielded few, if any, promising results. An alternative approach may be to target signaling events downstream of β-amyloid and even tau. However, with so many pathways already linked to the disease, understanding which ones are "drivers" versus "passengers" in the pathogenesis of the disease remains a tremendous challenge. Given the critical roles of Rho-guanosine triphosphatases (GTPases) in regulating the actin cytoskeleton and spine dynamics, and the strong association between spine abnormalities and cognition, it is not surprising that mutations in a number of genes involved in RhoGTPase signaling have been implicated in several brain disorders, including schizophrenia and autism. And now, there is mounting literature implicating Rho-GTPase signaling in AD pathogenesis as well. Here, I review this evidence, with a particular emphasis on the regulators of Rho-GTPase signaling, namely guanine nucleotide exchange factors and GTPaseactivating proteins. Several of these have been linked to various aspects of AD, and each offers a novel potential therapeutic target for AD.

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Decreased Dendritic Spine Density on Prefrontal Cortical Pyramidal Neurons in Schizophrenia

Cited by 1,440 publications

References 75 publications

Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

An integrated genomic analysis of gene-function correlation on schizophrenia susceptibility genes

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

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