Interneuron hypomyelination is associated with cognitive inflexibility in a rat model of schizophrenia

Maas, Dorien A.; Eijsink, V.D.; Spoelder, Marcia; Hulten, Josephus A. van; Weerd, Peter De; Homberg, Judith R.; Vallès, Astrid; Nait‐Oumesmar, Brahim; Martens, Gerard J.M.

doi:10.1038/s41467-020-16218-4

Cited by 49 publications

(59 citation statements)

References 70 publications

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“…Notably, the synchronization of neuronal ensembles in the gamma range frequency, which largely depends on FSI activity 50 , is commonly altered in this disease. Moreover, a recent study performed in a rat model of schizophrenia showed a hypomyelination of cortical PV + interneurons 51 . Considering our demonstration of the important role of FSI myelination in regulating the function of FSI, it is thus possible that FSI myelination defects alter local cortical circuit oscillations in vivo which, in turn, contribute to cognitive deficits observed in this disease 5,15 .…”

Section: Discussionmentioning

confidence: 98%

Myelination of parvalbumin interneurons shapes the function of cortical sensory inhibitory circuits

et al. 2020

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Myelination of projection neurons by oligodendrocytes is key to optimize action potential conduction over long distances. However, a large fraction of myelin enwraps the axons of parvalbumin-positive fast-spiking interneurons (FSI), exclusively involved in local cortical circuits. Whether FSI myelination contributes to the fine‐tuning of intracortical networks is unknown. Here we demonstrate that FSI myelination is required for the establishment and maintenance of the powerful FSI-mediated feedforward inhibition of cortical sensory circuits. The disruption of GABAergic synaptic signaling of oligodendrocyte precursor cells prior to myelination onset resulted in severe FSI myelination defects characterized by longer internodes and nodes, aberrant myelination of branch points and proximal axon malformation. Consequently, high-frequency FSI discharges as well as FSI-dependent postsynaptic latencies and strengths of excitatory neurons were reduced. These dysfunctions generated a strong excitation-inhibition imbalance that correlated with whisker-dependent texture discrimination impairments. FSI myelination is therefore critical for the function of mature cortical inhibitory circuits.

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Section: Discussionmentioning

confidence: 98%

Myelination of parvalbumin interneurons shapes the function of cortical sensory inhibitory circuits

et al. 2020

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“…About half of the dry weight of the brain is attributable to lipids and about 80% of brain lipids are part of myelin sheaths. In SZ PFC, abnormalities in myelination are evident and decreased PFC myelin content contributes to disease symptomatology 76 , 77 . Furthermore, polyunsaturated fatty acid levels in the blood are correlated with white-matter integrity in frontal regions of the SZ brain 78 , whereas increased LDL levels are associated with white-matter alterations 79 , and white matter, as well as myelin abnormalities in the PFC contribute to cognitive deficits in SZ 76 .…”

Section: Discussionmentioning

confidence: 99%

Key role for lipids in cognitive symptoms of schizophrenia

Maas

Martens²,

Priovoulos

et al. 2020

Transl Psychiatry

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Schizophrenia (SZ) is a psychiatric disorder with a convoluted etiology that includes cognitive symptoms, which arise from among others a dysfunctional dorsolateral prefrontal cortex (dlPFC). In our search for the molecular underpinnings of the cognitive deficits in SZ, we here performed RNA sequencing of gray matter from the dlPFC of SZ patients and controls. We found that the differentially expressed RNAs were enriched for mRNAs involved in the Liver X Receptor/Retinoid X Receptor (LXR/RXR) lipid metabolism pathway. Components of the LXR/RXR pathway were upregulated in gray matter but not in white matter of SZ dlPFC. Intriguingly, an analysis for shared genetic etiology, using two SZ genome-wide association studies (GWASs) and GWAS data for 514 metabolites, revealed genetic overlap between SZ and acylcarnitines, VLDL lipids, and fatty acid metabolites, which are all linked to the LXR/RXR signaling pathway. Furthermore, analysis of structural T1-weighted magnetic resonance imaging in combination with cognitive behavioral data showed that the lipid content of dlPFC gray matter is lower in SZ patients than in controls and correlates with a tendency towards reduced accuracy in the dlPFC-dependent task-switching test. We conclude that aberrations in LXR/RXR-regulated lipid metabolism lead to a decreased lipid content in SZ dlPFC that correlates with reduced cognitive performance.

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“…Moreover, ultrastructural analysis showed that the mitochondrial surface in the mPFC of NAC-treated APO-SUS and APO-UNSUS rats was decreased ( Fig. 2e; Two-way ANOVA interaction F [1,17] NAC treatment improves hypomyelination in APO-SUS mPFC Hypomyelination of mPFC interneurons occurs in APO-SUS rats during adolescence [16]. Oxidative stress is thought to affect the maturation of PFC interneurons in adolescent SZ patients [22].…”

Section: Nac Treatment Alleviates Oxidative Stress In Apo-sus Mpfcmentioning

confidence: 95%

Antioxidant treatment ameliorates prefrontal hypomyelination and cognitive deficits in a rat model of schizophrenia

Maas

Eijsink

Hulten

et al. 2021

Neuropsychopharmacol.

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Cognitive dysfunction in schizophrenia (SZ) is thought to arise from neurodevelopmental abnormalities that include interneuron hypomyelination in the prefrontal cortex (PFC). Here we report that RNA-sequencing of the medial (m)PFC of the APO-SUS rat model with SZ-relevant cognitive inflexibility revealed antioxidant metabolism as the most-enriched differentially expressed pathway. Antioxidant-related gene expression was altered throughout postnatal development and preceded hypomyelination. Furthermore, reduced glutathione levels and increased mitochondria numbers were observed in the mPFC. Strikingly, chronic treatment with the glutathione precursor N-acetylcysteine (NAC) from postnatal days 5–90 restored not only antioxidant-related mRNA expression and mitochondria numbers, but also myelin-related mRNA expression and mPFC-dependent cognitive dysfunction, while blood glutathione levels remained unaffected. The promyelinating effect of NAC was at least partly due to a positive effect on oligodendrocyte lineage progression. Together, our findings highlight that oxidative stress may contribute to cognitive symptoms in the APO-SUS rat model of SZ and encourage antioxidant therapy in early phases of SZ.

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Interneuron hypomyelination is associated with cognitive inflexibility in a rat model of schizophrenia

Cited by 49 publications

References 70 publications

Myelination of parvalbumin interneurons shapes the function of cortical sensory inhibitory circuits

Myelination of parvalbumin interneurons shapes the function of cortical sensory inhibitory circuits

Key role for lipids in cognitive symptoms of schizophrenia

Antioxidant treatment ameliorates prefrontal hypomyelination and cognitive deficits in a rat model of schizophrenia

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