Sex-specific microglia state in the Neuroligin-4 knock-out mouse model of autism spectrum disorder

Güneykaya, Dilansu; Ugursu, Bilge; Logiacco, Francesca; Popp, Oliver; Feiks, Maria Almut; Meyer, Niklas; Wendt, Stefan; Semtner, Marcus; Cherif, Fatma; Gauthier, Christian; Madore, Charlotte; Yin, Zhuoran; Çınar, Özcan; Arslan, Taner; Gerevich, Zoltán; Mertins, Philipp; Butovsky, Oleg; Kettenmann, Helmut; Wolf, Susanne

doi:10.1016/j.bbi.2023.03.023

Cited by 16 publications

(12 citation statements)

References 74 publications

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“…Sex-related differences in brain organization have been described in nonpathological mammals; for instance, in rats, the medial preoptic nucleus, the bed nucleus of the stria terminalis, and the medial amygdala displayed a larger volume in males compared to females (Gorski et al, 1978;Hines et al, 1992). In the CA3hippocampal region of WT male mice, a higher microglia density was found compared with females (Guneykaya et al, 2023). In humans, neuroimaging studies have indicated differences in grey matter volume between males and females in various cortical areas (Kaczkurkin et al, 2018;Ruigroket et al, 2014), similar results…”

Section: Discussionmentioning

confidence: 98%

“…The "astrocytosis" observed in both sexes of En2 −/− mice was accompanied by an increase of microglial cells in females only. Sexdependent changes in microglia have been described in the hippocampus of NLGN4 −/− mice, a model of ASD, where a decrease in the density of Iba1-ir microglia has been reported only in males (Guneykaya et al, 2023). In postmortem human subjects (males) with ASD, an increase in microglia was described in various brain areas (Menassa et al, 2017;Tetreault et al, 2012;Vargas et al, 2005), in particular, Vargas et al (2005) found significantly higher microglial immunoreactivity in the cerebellum of autistic brains.…”

Section: Discussionmentioning

confidence: 99%

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Glial cells are affected more than interneurons by the loss of Engrailed 2 gene in the mouse cerebellum

Lazzarini,

Gatta,

Miragliotta

et al. 2023

Journal of Anatomy

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Glial cells play a pivotal role in the inflammatory processes, which are common features of several neurodevelopmental and neurodegenerative disorders. Their major role in modulating neuroinflammation underscores their significance in these conditions. Engrailed‐2 knockout mice (En2−/−) are considered a valuable model for autism spectrum disorder (ASD) due to their distinctive neuroanatomical and behavioral traits. Given the higher prevalence of ASD in males, our objective was to investigate glial and interneuron alterations in the cerebellum of En2−/− mice compared with wild‐type (WT) mice in both sexes. We employed immunohistochemical analysis to assess cell density for all cell types studied and analyzed the area (A) and shape factor (SF) of microglia cell bodies. Our findings revealed the following: (a) In WT mice, the density of microglia and astrocytes was higher in females than in males, while interneuron density was lower in females. Notably, in En2‐mutant mice, these differences between males and females were not present. (b) In both male and female En2−/− mice, astrocyte density exceeded that in WT mice, with microglia density being greater only in females. (c) In WT females, microglia cell bodies exhibited a larger area and a lower shape factor compared to WT males. Remarkably, the En2 mutation did not appear to influence these sex‐related differences. (d) In both male and female En2−/− mice, we observed a consistent pattern: microglia cell bodies displayed a larger area and a smaller shape factor. Given the ongoing debate surrounding the roles of glia and sex‐related factors in ASD, our observations provide valuable insights into understanding how an ASD‐associated gene En2 affects specific cell types in the cerebellum.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Glial cells are affected more than interneurons by the loss of Engrailed 2 gene in the mouse cerebellum

Lazzarini,

Gatta,

Miragliotta

et al. 2023

Journal of Anatomy

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“…Deletion of neuroligin-4, a protein expressed by neurons and not by microglia, is linked to autism spectrum disorders and has a gender-specific impact on microglia. Male microglia show a lower cell density, a less ramified morphology, a reduced response to injury and purinergic signaling specifically in the hippocampal CA3 region (Guneykaya et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

TREM2 promotes glioma progression and angiogenesis mediated by microglia/brain macrophages

Chen,

Zhao,

Huang

et al. 2023

Glia

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Triggering receptor expressed on myeloid cell 2 (TREM2), a myeloid cell‐specific signaling molecule, controls essential functions of microglia and impacts on the pathogenesis of Alzheimer's disease and other neurodegenerative disorders. TREM2 is also highly expressed in tumor‐associated macrophages in different types of cancer. Here, we studied whether TREM2 influences glioma progression. We found a gender‐dependent effect of glioma growth in wild‐type (WT) animals injected with GL261‐EGFP glioma cells. Most importantly, TREM2 promotes glioma progression in male but not female animals. The accumulation of glioma‐associated microglia/macrophages (GAMs) and CD31+ blood vessel density is reduced in male TREM2‐deficient mice. A transcriptomic analysis of glioma tissue revealed that TREM2 deficiency suppresses immune‐related genes. In an organotypic slice model devoid of functional vascularization and immune components from periphery, the tumor size was not affected by TREM2‐deficiency. In human resection samples from glioblastoma, TREM2 is upregulated in GAMs. Based on the Cancer Genome Atlas Program (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases, the TREM2 expression levels were negatively correlated with survival. Thus, the TREM2‐dependent crosstalk between GAMs and the vasculature formation promotes glioma growth.

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“…Guneykaya et al. ( 178 ) found that hippocampal γ-oscillations were disrupted and hippocampal microglia density was reduced only in male Nlgn4 KO mice. Hence, contradictory results in the hippocampal inhibitory state may partly be explained by sex-dependent and age-related impacts of Nlgn4 loss.…”

Section: Abnormalities In the Structure And Function Of The Hippocamp...mentioning

confidence: 99%

Insights into the structure and function of the hippocampus: implications for the pathophysiology and treatment of autism spectrum disorder

Long,

Li,

Liu

et al. 2024

Front. Psychiatry

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The hippocampus is one of the brain areas affected by autism spectrum disorder (ASD). Individuals with ASD typically have impairments in hippocampus-dependent learning, memory, language ability, emotional regulation, and cognitive map creation. However, the pathological changes in the hippocampus that result in these cognitive deficits in ASD are not yet fully understood. In the present review, we will first summarize the hippocampal involvement in individuals with ASD. We will then provide an overview of hippocampal structural and functional abnormalities in genetic, environment-induced, and idiopathic animal models of ASD. Finally, we will discuss some pharmacological and non-pharmacological interventions that show positive impacts on the structure and function of the hippocampus in animal models of ASD. A further comprehension of hippocampal aberrations in ASD might elucidate their influence on the manifestation of this developmental disorder and provide clues for forthcoming diagnostic and therapeutic innovation.

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Sex-specific microglia state in the Neuroligin-4 knock-out mouse model of autism spectrum disorder

Cited by 16 publications

References 74 publications

Glial cells are affected more than interneurons by the loss of Engrailed 2 gene in the mouse cerebellum

Glial cells are affected more than interneurons by the loss of Engrailed 2 gene in the mouse cerebellum

TREM2 promotes glioma progression and angiogenesis mediated by microglia/brain macrophages

Insights into the structure and function of the hippocampus: implications for the pathophysiology and treatment of autism spectrum disorder

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