NOS1AP protein levels are altered in BA46 and cerebellum of patients with schizophrenia

Hadzimichalis, Norell M.; Previtera, Michelle L.; Moreau, Michael P.; Li, Bo; Lee, Gum Hwa; Dulencin, Anna M.; Matteson, Paul G.; Buyske, Steven; Millonig, James H.; Brzustowicz, Linda M.; Firestein, Bonnie L.

doi:10.1016/j.schres.2010.05.009

Cited by 24 publications

(28 citation statements)

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“…It is also hypothesized that NMDA receptor signaling is decreased in patients with schizophrenia, known as the NMDA receptor hypofunction hypothesis (recently reviewed in (30)). Overexpression of NOS1AP, as is seen in brain tissue from patients with schizophrenia (4, 9), is consistent with this theory. Interestingly, the NMDA receptor has been implicated in the regulation of cortical (31–32) and hippocampal(33) neuron migration via a pathway that includes Disrupted-in-Schizophrenia1 (DISC1)(33) and Reelin(34).…”

Section: Discussionsupporting

confidence: 74%

“…NOS1AP expression is significantly increased in the dorsolateral region of the prefrontal cortex in patients with schizophrenia (9). To investigate the role of NOS1AP overexpression during early cortical development, we performed in utero electroporation (IUE) experiments to introduce a construct expressing NOS1AP into neural progenitor cells of the embryonic rat neocortex.…”

Section: Resultsmentioning

confidence: 99%

“…It competes with PSD-95 for nNOS binding and presumably reduces NMDA receptor signaling via PSD-95 and nNOS. There are at least three isoforms of NOS1AP (long (L), short (S), and short’ (S’)) that have been reported to have altered protein expression in the cortex of individuals diagnosed with schizophrenia (9). Specifically, NOS1AP-L protein expression, normalized to the housekeeping protein GAPDH, is elevated approximately 10-fold whereas the other two isoforms are elevated approximately 100-fold (9).…”

Section: Introductionmentioning

confidence: 99%

“…There are at least three isoforms of NOS1AP (long (L), short (S), and short’ (S’)) that have been reported to have altered protein expression in the cortex of individuals diagnosed with schizophrenia (9). Specifically, NOS1AP-L protein expression, normalized to the housekeeping protein GAPDH, is elevated approximately 10-fold whereas the other two isoforms are elevated approximately 100-fold (9). In addition, NOS1AP-L mRNA expression is significantly decreased by 40% in postmortem brain tissue from patients treated with antipsychotics when compared to untreated patients with the same psychiatric diagnosis (4).…”

Section: Introductionmentioning

confidence: 99%

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Nitric Oxide Synthase 1 Adaptor Protein, a Protein Implicated in Schizophrenia, Controls Radial Migration of Cortical Neurons

Carrel

Hernandez

Kwon

et al. 2015

Biological Psychiatry

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Background Where a neuron is positioned in the brain during development determines neuronal circuitry and information processing needed for normal brain function. When aberrations in this process occur, cognitive disorders may result. Patients diagnosed with schizophrenia have been reported to show altered neuronal connectivity and heterotopias. To elucidate pathways by which this process occurs and become aberrant, we have chosen to study the long isoform of nitric oxide synthase 1 adaptor protein (NOS1AP), a protein encoded by a susceptibility gene for schizophrenia. Methods To determine whether NOS1AP plays a role in cortical patterning, we knocked down or co-overexpressed NOS1AP and a GFP or TagRFP reporter in neuronal progenitor cells of the embryonic rat neocortex using in utero electroporation. We analyzed sections of cortex (ventricular zone VZ, intermediate zone IZ, and cortical plate CP) containing GFP or TagRFP positive cells and counted the percentage of positive cells that migrated to each region from at least three rats for each condition. Results NOS1AP overexpression disrupts neuronal migration, resulting in increased cells in IZ and less cells in CP, and decreases dendritogenesis. Knock down results in increased migration, with more cells reaching the CP. The phosphotyrosine binding region, but not the PDZ-binding motif, is necessary for NOS1AP function. Amino acids 181–307, which are sufficient for NOS1AP-mediated decreases in dendrite number, have no effect on migration. Conclusions Our studies show for the first time a critical role for the schizophrenia-associated gene NOS1AP in cortical patterning, which may contribute to underlying pathophysiology seen in schizophrenia.

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Section: Discussionsupporting

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Nitric Oxide Synthase 1 Adaptor Protein, a Protein Implicated in Schizophrenia, Controls Radial Migration of Cortical Neurons

Carrel

Hernandez

Kwon

et al. 2015

Biological Psychiatry

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“…NOS1AP is a protein encoded by a schizophrenia susceptibility gene (Brzustowicz et al, 2000 ; Zheng et al, 2005 ; Miranda et al, 2006 ; Kremeyer et al, 2008 ; Wratten et al, 2009 ). We have previously shown that the expression of NOS1AP-L and NOS1AP-S is upregulated in postmortem tissue from the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia (Hadzimichalis et al, 2010 ). Since schizophrenia is believed to be a neurodevelopmental disorder (Benes, 1991 ; Murray et al, 1991 ; Bunney et al, 1995 ; Brent et al, 2014 ), in the present study, we investigate the effects of overexpression of these isoforms on actin dynamics, dendritic spine number and morphology, and resulting electrophysiology.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Isoforms of Nitric Oxide Synthase 1 Adaptor Protein, Encoded by a Risk Gene for Schizophrenia, Alters Actin Dynamics and Synaptic Function

Hernandez

Swiatkowski

Patel

et al. 2016

Front. Cell. Neurosci.

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Proper communication between neurons depends upon appropriate patterning of dendrites and correct distribution and structure of spines. Schizophrenia is a neuropsychiatric disorder characterized by alterations in dendrite branching and spine density. Nitric oxide synthase 1 adaptor protein (NOS1AP), a risk gene for schizophrenia, encodes proteins that are upregulated in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia. To elucidate the effects of NOS1AP overexpression observed in individuals with schizophrenia, we investigated changes in actin dynamics and spine development when a long (NOS1AP-L) or short (NOS1AP-S) isoform of NOS1AP is overexpressed. Increased NOS1AP-L protein promotes the formation of immature spines when overexpressed in rat cortical neurons from day in vitro (DIV) 14 to DIV 17 and reduces the amplitude of miniature excitatory postsynaptic currents (mEPSCs). In contrast, increased NOS1AP-S protein increases the rate of actin polymerization and the number of immature and mature spines, which may be attributed to a decrease in total Rac1 expression and a reduction in the levels of active cofilin. The increase in the number of mature spines by overexpression of NOS1AP-S is accompanied by an increase in the frequency of mEPSCs. Our findings show that overexpression of NOS1AP-L or NOS1AP-S alters the actin cytoskeleton and synaptic function. However, the mechanisms by which these isoforms induce these changes are distinct. These results are important for understanding how increased expression of NOS1AP isoforms can influence spine development and synaptic function.

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Genetic Intersections of Language and Neuropsychiatric Conditions

Koomar

Michaelson

2020

Curr Psychiatry Rep

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NOS1AP protein levels are altered in BA46 and cerebellum of patients with schizophrenia

Cited by 24 publications

References 10 publications

Nitric Oxide Synthase 1 Adaptor Protein, a Protein Implicated in Schizophrenia, Controls Radial Migration of Cortical Neurons

Nitric Oxide Synthase 1 Adaptor Protein, a Protein Implicated in Schizophrenia, Controls Radial Migration of Cortical Neurons

Overexpression of Isoforms of Nitric Oxide Synthase 1 Adaptor Protein, Encoded by a Risk Gene for Schizophrenia, Alters Actin Dynamics and Synaptic Function

Genetic Intersections of Language and Neuropsychiatric Conditions

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