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NPTX2, Homeostatic Scaling, and Schizophrenia

ABSTRACT: Schizophrenia is a complex genetic and developmental disorder. We present a model of disease resulting from disruption of a specific stage of homeostatic scaling (HS). HS modifies synapses and circuits in response to changes in neuronal activity and underlies cortical development and memory consolidation. Neuronal pentraxin 2 (NPTX2) plays a critical role in HS and its homeostatic action requires exocytosis at excitatory synapses on parvalbumin interneurons (PV) whereupon a portion is later shed into the CSF. CSF NPTX2 is reduced in two independent cohorts of patients with schizophrenia. To understand the relationship of this biomarker to disease we confirmed that in normal volunteers CSF NPTX2 increases rapidly with sleep deprivation consistent with behavior-linked exocytosis/shedding. In mouse neocortex NPTX2 exocytosis/shedding are activity-dependent and coupled to circadian behavioral. By contrast, in mouse genetic models that interrupt early events in HS NPTX2 exocytosis/shedding are erratic and not linked to behavior. The vital contribution of NPTX2 to homeostasis is revealed in Nptx2-/- mice, which exhibit sensitivity to social isolation stress and multiple schizophrenia-domain phenotypes. NPTX2 is not implicated by human genome studies; rather we propose that diverse mutations linked to schizophrenia disrupt activity-dependent mechanisms required for NPTX2 function. The ability to monitor NPTX2 in human subjects provides an opportunity to translate fundamental neuroscience to human neuropsychiatric disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE150671 | GEO | 2021/05/15

REPOSITORIES: GEO

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Project description:Gray matter volume in the cerebral cortex has been consistently found to be decreased in patients with schizophrenia. The superior temporal gyrus (STG) is one of the cortical regions that exhibit the most pronounced volumetric reduction. This reduction is generally thought to reflect, at least in part, decreased number of synapses; the majority of these synapses are believed to be furnished by glutamatergic axon terminals onto the dendritic spines on pyramidal neurons. Pyramidal neurons in the cerebral cortex exhibit layer-specific connectional properties, providing neural circuit structures that support distinct aspects of higher cortical functions. For instance, dendritic spines on pyramidal neurons in layer 3 of the cerebral cortex are targeted by both local and long-range glutamatergic projections in a highly reciprocal fashion. Synchronized activities of pyramidal neuronal networks, especially in the gamma frequency band (i.e. 30-100 Hz), are critical for the integrity of higher cortical functions. Disturbances of these networks may contribute to the pathophysiology of schizophrenia by compromising gamma oscillation. This concept is supported by the following postmortem and clinical observations. First, the density of dendritic spines on pyramidal neurons in layer 3 of the cerebral cortex, including the STG, have been shown to be significantly decreased by 23-66% in subjects with schizophrenia. Second, consistent with these findings, the average somal area of these pyramidal cells is significantly smaller. Third, we have recently found that, in the prefrontal cortex, the density of glutamatergic axonal boutons, of which dendritic spines are their major targets, was significantly decreased by as much as 79% in layer 3 (but not layer 5) in subjects with schizophrenia. Finally, an increasing number of clinical studies have consistently demonstrated that gamma oscillatory synchrony is profoundly impaired in patients with schizophrenia. Furthermore, gamma impairment has been linked to the symptoms and cognitive deficits of the illness and the severity of these symptoms and deficits have in turn been associated with the magnitude of cortical gray matter reduction. Taken together, understanding the molecular underpinnings of pyramidal cell dysfunction will shed important light onto the pathophysiology of cortical dysfunction of schizophrenia. In order to gain insight into the molecular determinants of pyramidal cell dysfunction in schizophrenia, we combined LCM with Affymetrix microarray and high-throughput TaqManM-BM-.-based MegaPlex qRT-PCR approaches, respectively, to elucidate the alterations in messenger ribonucleic acid (mRNA) and microRNA (miRNA) expression profiles of these neurons in layer 3 of the STG. We found that transforming growth factor beta (TGFM-NM-2) and BMP (bone morphogenetic proteins) signaling pathways and many genes that regulate extracellular matrix (ECM), apoptosis and cytoskeleton were dysregulated in schizophrenia. In addition, we identified 10 miRNAs that were differentially expressed in this illness; interestingly, the predicted targets of these miRNAs included the dysregulated pathways and gene networks identified by microarray analysis. Together these findings provide a neurobiological framework within which we can begin to formulate and test specific hypotheses about the molecular mechanisms that underlie pyramidal cell dysfunction in schizophrenia. Gene epxression microarray from RNA isolated from pyramidal cells in layer III of the STG from 9 normal controls and 9 subjects with schizophrenia. There was no significant difference between diagnosis groups for age, sex, and post mortem interval (PMI).

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NPTX2, Homeostatic Scaling, and Schizophrenia

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