Inflammation-related pathology in the olfactory epithelium: its impact on the olfactory system in psychotic disorders

Yang, Kun; Hasegawa, Yuto; Bhattarai, Janardhan P.; Hua, Jun; Dower, Milan; Etyemez, Semra; Prasad, Neal; Duvall, Lauren; Paez, Adrian; Smith, Amy; Wang, Yingqi; Zhang, Yun-Feng; Lane, Andrew P.; Ishizuka, Koko; Kamath, Vidyulata; Ma, Minghong; Kamiya, Atsushi; Sawa, Akira

doi:10.1038/s41380-024-02425-8

Cited by 4 publications

(4 citation statements)

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“…Olfactory impairment has been suggested as an early indicator for several neuropsychiatric disorders, such as schizophrenia and psychosis [26–28]. Patients with first episode psychosis were shown to display deficits in odor identification tasks, and a reduced OB volume and inflammation of the olfactory epithelium have been associated with schizophrenia [28,30]. We found largely normal odor detection and odor learning in GE mice consistent with normal odor-evoked activity during development, but long-term odor memory was impaired.…”

Section: Discussionmentioning

confidence: 99%

“…Both, WT and GE mice showed continuous activity in the local field potential (LFP) recorded in the OB with the typical dominant respiration rhythm (RR, 2-4 Hz) that reverses polarity at the MCL (Fig 2C). However, the power in RR and theta (4-12 Hz) frequency bands were significantly reduced in GE mice (RR p=5.1x10 -4 , theta p=0.004), whereas the power in beta (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) was not significantly different (p=0.09) (Fig 2D). Further, the firing rate of single units in the OB was reduced in GE mice, particularly for neurons in the MCL (MCL p=0.023; GCL p=0.51), indicating a reduction in the activity of OB projection neurons in the absence of odor stimulation (Fig 2E).…”

Section: Reduced Ob Activity In Immune-challenged Disc1 +/Mice During...mentioning

confidence: 91%

“…Time-frequency power plots were calculated with a continuous wavelet transform (Morlet wavelet). Frequency bands for statistical comparisons were defined as RR (2-4 Hz), theta (4-12 Hz) and beta (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Frequency resolved amplitude correlation.…”

Section: Analysis Of Electrophysiological Datamentioning

confidence: 99%

“…Accumulating evidence suggests an association of olfactory impairment with neuropsychiatric disorders. For example, inflammation of the olfactory epithelium, reduced OB volume, and deficits in odor perception have been reported for schizophrenia, psychosis, and depression [26][27][28][29][30]. However, it is unknown how alterations in the olfactory system might contribute to the pathogenesis of neuropsychiatric disorders that involve prefrontal-hippocampal dysfunction [24,31].…”

Section: Introductionmentioning

confidence: 99%

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Developmental olfactory dysfunction and abnormal odor memory in immune-challengedDisc1^+/-mice

Parbst,

Kostka,

Günther

et al. 2024

Preprint

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Neuronal activity in the olfactory bulb (OB) drives coordinated activity in the hippocampal-prefrontal network during early development. Inhibiting OB output in neonatal mice disrupts functional development of the hippocampal formation as well as cognitive abilities. These impairments manifest early in life and resemble dysfunctions of the hippocampus and the prefrontal cortex that have been linked to neuropsychiatric disorders. Thus, we investigated a disease mouse model and asked whether activity in the OB might be altered, thereby contributing to the dysfunctional development of the hippocampal-prefrontal network. We addressed this question by combining in vivo electrophysiology with behavioral assessment of immune-challenged Disc1+/- mice that mimic the dual genetic-environmental etiology of neuropsychiatric disorders. In wildtype mice, we found high DISC1 expression levels in OB projection neurons during development. Furthermore, neuronal and network activity in the OB, as well as the drive from the bulb to the hippocampal-prefrontal network were reduced in immune-challenged Disc1+/- mice during early development. This early deficit did not affect odor-evoked activity and odor perception but resulted in impaired long-term odor memory. We propose that reduced endogenous activity in the developing OB contributes to altered maturation of the hippocampal-prefrontal network, leading to memory impairment in immune-challenged Disc1+/- mice.

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Section: Discussionmentioning

confidence: 99%

Section: Reduced Ob Activity In Immune-challenged Disc1 +/Mice During...mentioning

confidence: 91%

Section: Analysis Of Electrophysiological Datamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Developmental olfactory dysfunction and abnormal odor memory in immune-challengedDisc1^+/-mice

Parbst,

Kostka,

Günther

et al. 2024

Preprint

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SCG2 mediates blood–brain barrier dysfunction and schizophrenia‐like behaviors after traumatic brain injury

Lin,

Zhao,

Sun

et al. 2024

The FASEB Journal

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Traumatic brain injury (TBI), which is characterized by acute neurological dysfunction, is also one of the most widely recognized environmental risk factors for various neurological and psychiatric disorders. However, the role of TBI in neurological perturbation and the mechanisms underlying these disorders remain unknown. We evaluated transcriptional changes in cells of the frontal cortex after TBI by exploiting single‐cell RNA sequencing (scRNA‐Seq). We adopted the gene expression omnibus and scRNA‐Seq to identify the mediation by secretogranin II (SCG2) of TBI‐induced schizophrenia. Astrocytes are a principal source of SCG2 in the frontal cortex after TBI. Our analysis indicated that SCG2‐triggered disruption of the blood–brain barrier (BBB) via the CypA‐MMP‐9 signaling pathway. Furthermore, astrocytic SCG2 knockout in the frontal cortex reduced BBB damage, mitigated inflammation, and inhibited schizophrenia after TBI. In conclusion, we identified the SCG2‐CypA‐MMP‐9 signaling pathway in reactive astrocytes as a key switch in the protection of the BBB and provided a novel therapeutic avenue for treating psychiatric disorders after TBI.

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The IL‐4–IL‐4Rα axis modulates olfactory neuroimmune signaling to induce loss of smell

Hara,

Jha,

Huang

et al. 2024

Allergy

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BackgroundLoss of smell is a part of the diagnostic criteria for CRSwNP. Although the mechanistic understanding is poor, inhibition of IL‐4Rα and IL‐4/IL‐13 signaling improves loss of smell in CRSwNP patients. In the present study, we compare the effects of IL‐4, IL‐13, and IL‐4Rα blockade on murine olfaction and identify the underlying pathophysiological mechanisms of loss of smell.MethodsTo evaluate the effects of IL‐4 and IL‐13 on olfactory function, we administered these cytokines intranasally to BALB/c mice for 5 consecutive days and assessed their latency to find hidden food. Calcium uptake assays were conducted to measure olfactory neuronal activity in vitro and ex vivo. We also performed histological analyses, proteomics, bulk RNA sequencing, and single‐cell RNA sequencing to assess the impact of IL‐4, IL‐13, and IL‐4Rα blockade on the olfactory epithelium and to identify potential molecular or cellular correlations with smell loss in human CRSwNP patients.ResultsHere, we provide evidence for non‐redundant effects of IL‐4 and IL‐13 in olfaction, with loss of smell in mice evoked by intranasal administration of IL‐4, not IL‐13. We demonstrate that an IL‐4–IL‐4Rα axis has a direct functional impact on murine olfactory sensory neurons and evokes inflammatory cell infiltration and pathophysiologic modulation of unique molecular signatures in olfactory epithelium without compromising structural integrity. Furthermore, single‐cell analysis of olfactory epithelium reveals that IL‐4–IL‐4Rα signaling modulates neuronal crosstalk with mast cells, macrophages, and NK cells, suggesting a functional link between olfactory impairment and neuroinflammation.ConclusionCollectively, this study suggests that an IL‐4–IL‐4Rα signaling axis plays a unique pathophysiological role in olfactory dysfunction via direct effect on neurons and modulation of neuroimmune interactions.

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Inflammation-related pathology in the olfactory epithelium: its impact on the olfactory system in psychotic disorders

Cited by 4 publications

References 70 publications

Developmental olfactory dysfunction and abnormal odor memory in immune-challengedDisc1^+/-mice

Developmental olfactory dysfunction and abnormal odor memory in immune-challengedDisc1^+/-mice

SCG2 mediates blood–brain barrier dysfunction and schizophrenia‐like behaviors after traumatic brain injury

The IL‐4–IL‐4Rα axis modulates olfactory neuroimmune signaling to induce loss of smell

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Inflammation-related pathology in the olfactory epithelium: its impact on the olfactory system in psychotic disorders

Cited by 4 publications

References 70 publications

Developmental olfactory dysfunction and abnormal odor memory in immune-challengedDisc1+/-mice

Developmental olfactory dysfunction and abnormal odor memory in immune-challengedDisc1+/-mice

SCG2 mediates blood–brain barrier dysfunction and schizophrenia‐like behaviors after traumatic brain injury

The IL‐4–IL‐4Rα axis modulates olfactory neuroimmune signaling to induce loss of smell

Contact Info

Product

Resources

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Developmental olfactory dysfunction and abnormal odor memory in immune-challengedDisc1^+/-mice

Developmental olfactory dysfunction and abnormal odor memory in immune-challengedDisc1^+/-mice