NGPF2 triggers synaptic scaling up through ALK-LIMK-cofilin-mediated mechanisms

Zhou, Zikai; He, Guiqin; Zhang, Xiaoyun; Lv, Xin; Zhang, Xiaolin; Liu, An; Xia, Shuting; Xie, Hao; Dang, Rui; Han, Lifang; Qi, Junxia; Meng, Yanghong; Yu, Shunying; Xie, Wei; Jia, Zhengping

doi:10.1016/j.celrep.2021.109515

Cited by 9 publications

(6 citation statements)

References 70 publications

(85 reference statements)

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“…Neuroinflammation is thought to contribute to aging and age-related cognitive impairment by damaging hippocampal synaptic function ( Vanguilder and Freeman, 2011 ; Bettio et al, 2017 ; Juan and Adlard, 2019 ). The neurite growth-promoting factor 2 (NGPF2; also referred to as midkine) is not only a cytokine but also a neurotrophic factor ( Ross-Munro et al, 2020 ; Zhou et al, 2021 ). It is principally expressed in the developing central nervous system (CNS; Zhou et al, 2021 ) and is usually reduced to negligible level in adulthood ( Yoshida et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

“…The neurite growth-promoting factor 2 (NGPF2; also referred to as midkine) is not only a cytokine but also a neurotrophic factor ( Ross-Munro et al, 2020 ; Zhou et al, 2021 ). It is principally expressed in the developing central nervous system (CNS; Zhou et al, 2021 ) and is usually reduced to negligible level in adulthood ( Yoshida et al, 2014 ). However, mounting evidence indicates that NGPF2 is markedly upregulated in many pathological conditions that are characterized by inflammatory injury.…”

Section: Introductionmentioning

confidence: 99%

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Environmental enrichment improves declined cognition induced by prenatal inflammatory exposure in aged CD-1 mice: Role of NGPF2 and PSD-95

Zhang²,

Li³

et al. 2022

Front. Aging Neurosci.

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IntroductionResearch suggests that prenatal inflammatory exposure could accelerate age-related cognitive decline that may be resulted from neuroinflammation and synaptic dysfunction during aging. Environmental enrichment (EE) may mitigate the cognitive and synaptic deficits. Neurite growth-promoting factor 2 (NGPF2) and postsynaptic density protein 95 (PSD-95) play critical roles in neuroinflammation and synaptic function, respectively.MethodsWe examined whether this adversity and EE exposure can cause alterations in Ngpf2 and Psd-95 expression. In this study, CD-1 mice received intraperitoneal injection of lipopolysaccharide (50 μg/kg) or normal saline from gestational days 15–17. After weaning, half of the male offspring under each treatment were exposed to EE. The Morris water maze was used to assess spatial learning and memory at 3 and 15 months of age, whereas quantitative real-time polymerase chain reaction and Western blotting were used to measure hippocampal mRNA and protein levels of NGPF2 and PSD-95, respectively. Meanwhile, serum levels of IL-6, IL-1β, and TNF-α were determined by enzyme-linked immunosorbent assay.ResultsThe results showed that aged mice exhibited poor spatial learning and memory ability, elevated NGPF2 mRNA and protein levels, and decreased PSD-95 mRNA and protein levels relative to their young counterparts during natural aging. Embryonic inflammatory exposure accelerated age-related changes in spatial cognition, and in Ngpf2 and Psd-95 expression. Additionally, the levels of Ngpf2 and Psd-95 products were significantly positively and negatively correlated with cognitive dysfunction, respectively, particularly in prenatal inflammation-exposed aged mice. Changes in serum levels of IL-6, IL-1β, and TNF-α reflective of systemic inflammation and their correlation with cognitive decline during accelerated aging were similar to those of hippocampal NGPF2. EE exposure could partially restore the accelerated decline in age-related cognitive function and in Psd-95 expression, especially in aged mice.DiscussionOverall, the aggravated cognitive disabilities in aged mice may be related to the alterations in Ngpf2 and Psd-95 expression and in systemic state of inflammation due to prenatal inflammatory exposure, and long-term EE exposure may ameliorate this cognitive impairment by upregulating Psd-95 expression.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Environmental enrichment improves declined cognition induced by prenatal inflammatory exposure in aged CD-1 mice: Role of NGPF2 and PSD-95

Zhang²,

Li³

et al. 2022

Front. Aging Neurosci.

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“…This suggests that in single mutant adults, compensatory mechanisms such as re‐wiring of neuronal circuits can overcome the severity of the defect. It is also possible that there are Igf1‐r independent, but redundant Ltk/Alk pathways that result in the behavioral defects only observed in the DKOs, such as the recently reported ALK‐LIMK‐cofilin pathway, which regulates synaptic scaling (Zhou et al , 2021). Interestingly, in the Golgi‐stained sections (Fig 3E), we noticed that there appeared to be a reduction in the number of dendritic spines in DKO versus WT mice.…”

Section: Discussionmentioning

confidence: 99%

LTK and ALK promote neuronal polarity and cortical migration by inhibiting IGF1R activity

Christova

Liu

et al. 2023

EMBO Reports

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The establishment of axon‐dendrite polarity is fundamental for radial migration of neurons, cortical patterning, and formation of neuronal circuits. Here, we show that the receptor tyrosine kinases, Ltk and Alk, are required for proper neuronal polarization. In isolated primary mouse embryonic neurons, the loss of Ltk and/or Alk causes a multiple axon phenotype. In mouse embryos and newborn pups, the absence of Ltk and Alk delays neuronal migration and subsequent cortical patterning. In adult cortices, neurons with aberrant neuronal projections are evident and axon tracts in the corpus callosum are disrupted. Mechanistically, we show that the loss of Alk and Ltk increases the cell‐surface expression and activity of the insulin‐like growth factor 1 receptor (Igf‐1r), which activates downstream PI3 kinase signaling to drive the excess axon phenotype. Our data reveal Ltk and Alk as new regulators of neuronal polarity and migration whose disruption results in behavioral abnormalities.

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“…NRG1 deficiency or CRD-NRG1 overexpression in cortical projection neurons results in enhanced GABAergic inhibitory neurotransmission, thereby causing imbalance of excitatory-Inhibitory neurotransmission and altered LTP ( Agarwal et al, 2014 ). Nevertheless, one possibility that NRG1 regulates LTP through an excitatory neuron-intrinsic mechanism cannot be excluded, as a recent study reported that overexpression of NRG1 in forebrain excitatory neuron in ctoNrg1 mice that mimic the upregulated level of NRG1 in schizophrenic patients, results in decreased spine density and impaired glutamatergic neurotransmission in hippocampus CA1 and PFC via activation of LIMK1 and subsequent inactivation of p-cofilin ( Chen et al, 2021 ), which are essential for AMPAR stabilization at synapse and various forms of synaptic plasticity ( Ben Zablah et al, 2021 , Zhou et al, 2021 ).…”

Section: Schizophrenia Risk Genes Play Essential Roles In Synaptic Pl...mentioning

confidence: 99%

Publishers note

Zhang

Liao²,

Wen³

et al. 2022

IBRO Neuroscience Reports

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NGPF2 triggers synaptic scaling up through ALK-LIMK-cofilin-mediated mechanisms

Abstract: Highlights d Activity blockade by TTX induces rapid and transient release of NGPF2 d NGPF2 is necessary and sufficient for synaptic scaling up d NGPF2 triggers synaptic scaling up through ALK-LIMKcofilin pathway d NGPF2 synthesis requires FMRP1

Cited by 9 publications

References 70 publications

Environmental enrichment improves declined cognition induced by prenatal inflammatory exposure in aged CD-1 mice: Role of NGPF2 and PSD-95

Environmental enrichment improves declined cognition induced by prenatal inflammatory exposure in aged CD-1 mice: Role of NGPF2 and PSD-95

LTK and ALK promote neuronal polarity and cortical migration by inhibiting IGF1R activity

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