A biomarker-authenticated model of schizophrenia implicating NPTX2 loss of function.
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ABSTRACT:
SUBMITTER: Xiao MF
PROVIDER: S-EPMC8612534 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
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Project description:NPTX2, Homeostatic Scaling, and Schizophrenia
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Project description:A quantitative cortical model is developed, based on both computational and simulation approaches, which relates measured changes in cortical activity of gray matter with changes in the integrity of longitudinal fiber pathways. The model consists of modules of up to 5,000 neurons each, 80% excitatory and 20% inhibitory, with these having different degrees of synaptic connectiveness both within a module as well as between modules. It is shown that if the inter-modular synaptic connections are reduced to zero while maintaining the intra-modular synaptic connections constant, then activity in the modules is reduced by about 50%. This agrees with experimental observations in which cortical electrical activity in a region of interest, measured using the rate of oxidative glucose metabolism (CMRglc(ox)), is reduced by about 50% when the cortical region is isolated, either by surgical means or by transient cold block. There is also a 50% decrease in measured cortical activity following inactivation of the nucleus of Meynert and the intra-laminar nuclei of the thalamus, which arise either following appropriate lesions or in sleep. This occurs in the model if the inter-modular synaptic connections require input from these nuclei in order to function. In schizophrenia there is a 24% decrease in functional anisotropy of longitudinal fasciculi accompanied by a 7% decrease in cortical activity (CMRglc(ox)).The cortical model predicts this, namely for a 24% decrease in the functioning of the inter-modular connections, either through the complete loss of 24% of axons subserving the connections or due to such a decrease in the efficacy of all the inter-modular connections, there will be about a 7% decrease in the activity of the modules. This work suggests that deterioration of longitudinal fasciculi in schizophrenia explains the loss of activity in the gray matter.
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Project description:Memory loss in Alzheimer's disease (AD) is attributed to pervasive weakening and loss of synapses. Here, we present findings supporting a special role for excitatory synapses connecting pyramidal neurons of the hippocampus and cortex with fast-spiking parvalbumin (PV) interneurons that control network excitability and rhythmicity. Excitatory synapses on PV interneurons are dependent on the AMPA receptor subunit GluA4, which is regulated by presynaptic expression of the synaptogenic immediate early gene NPTX2 by pyramidal neurons. In a mouse model of AD amyloidosis, Nptx2-/- results in reduced GluA4 expression, disrupted rhythmicity, and increased pyramidal neuron excitability. Postmortem human AD cortex shows profound reductions of NPTX2 and coordinate reductions of GluA4. NPTX2 in human CSF is reduced in subjects with AD and shows robust correlations with cognitive performance and hippocampal volume. These findings implicate failure of adaptive control of pyramidal neuron-PV circuits as a pathophysiological mechanism contributing to cognitive failure in AD.
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Project description:The edited lines introduced a premature termination at rs757148409/p.Arg89Ter. The mutant iNs showed a ~50% decrease in OTUD7A protein expression without undergoing nonsense-mediated mRNA decay. The mutant iNs also exhibited marked reduction of dendritic complexity, synaptic puncta density of AMPA receptor subunit GluA1 and postsynaptic scaffold PSD-95, as well as neural firing rate and network activity. Congruent with the neural phenotypic alterations in mutant iNs, our transcriptomic analysis showed that the set of OTUD7A LoF downregulated genes was significantly enriched for synapse development and function, and was associated with SZ and other neuropsychiatric disorders. These results suggest that the OTUD7A LoF mutation rs757148409 impairs neurodevelopment and synaptic function in human neurons, providing mechanistic insight into the possible role of OTUD7A in driving neuropsychiatric phenotypes associated with the 15q13.3 microdeletion.
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