Interneuron Accumulation of Phosphorylated tau Impairs Adult Hippocampal Neurogenesis by Suppressing GABAergic Transmission

Zheng, Jie; Li, Honglian; Tian, Na; Liu, Fei; Wang, Lu; Yin, Yulong; Yue, Lupeng; Ma, Longyu; Wan, You; Wang, Jian‐Zhi

doi:10.1016/j.stem.2019.12.015

Cited by 107 publications

(94 citation statements)

References 74 publications

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“…For instance, GSK-3β overactivation or accumulation might accelerate the depletion of NSC pool and impair AHN through inducing the hyperphosphorylation of tau, a microtubule-associated protein plays pivotal roles in shaping AHN 46 - 48 , since tau hyperphosphorylation has been widely accepted as one of hallmarks of accelerated aging and neurodegenerative diseases 49 . We have recently evidenced in a parallel study that accumulation of phosphorylated tau in GABAergic interneurons in the neurogenic niche induced AHN deficits, by disinhibiting local neural circuits and increasing NSC-derived astrogliosis 50 . However, whether and how tau hyperphosphorylation by GSK-3β in NSCs determines AHN, especially during accelerated senescence, remains unknown.…”

Section: Discussionmentioning

confidence: 96%

GSK-3β activation accelerates early-stage consumption of Hippocampal Neurogenesis in senescent mice

Liu¹,

Tian²,

Zhang³

et al. 2020

Theranostics

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Adult hippocampal neurogenesis (AHN) deficits contribute to the progression of cognitive impairments during accelerated senescence, with the mechanistic causes poorly understood. Glycogen synthase kinase-3β (GSK-3β) is a critical regulator in prenatal neurodevelopment. The present study aims to study whether and how GSK-3β regulates AHN during the accelerated senescence. Methods: AHN and AHN-dependent cognition and GSK-3β were evaluated in 3- and 6-month senescence-accelerated mice prone 8 (SAM-P8) and senescence resistant 1 (SAM-R1) mice, respectively. GSK-3β was selectively overexpressed in wild-type mice using adeno-associated virus, or knocked-out by crossbreeding with GSK-3β floxed mice in the neural stem cells (NSCs) of Nestin-Cre mice, or pharmacologically inhibited with SB216763 in SAM-P8 mice. AHN was evaluated by BrdU-, DCX-staining and retrovirus-labeling. Results: AHN transiently increased at 3-month, but dramatically dropped at 6-month of age in SAM-P8 mice with a simultaneous activation of GSK-3β at 3-month. Selective overexpression of GSK-3β in hippocampal NSCs of wildtype mice induced long-term AHN deficits due to an accelerated depletion of NSC pool, although it transiently increased the proliferation and survival of the newborn neurons. Pharmacologically inhibiting GSK-3β by SB216763 efficiently preserved AHN and improved contextual memory in 6-month SAM-P8 mice, while conditional knock-out of GSK-3β in NSCs impaired AHN. Conclusion: Early-stage activation of GSK-3β in NSCs impairs AHN by accelerating the depletion of NSC pool, and pharmacological inhibition of GSK-3β is efficient to preserve AHN during the accelerated aging. These results reveal novel mechanisms underlying the AHN impairments during accelerated senescence and provide new targets for pro-neurogenic therapies for related diseases.

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Section: Discussionmentioning

confidence: 96%

GSK-3β activation accelerates early-stage consumption of Hippocampal Neurogenesis in senescent mice

Liu¹,

Tian²,

Zhang³

et al. 2020

Theranostics

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“…On the other hand, elimination of young adult-generated granule cells increases overall DG excitability [ 63 ] and gamma network activity [ 64 ]. Meanwhile, local PV+ interneurons in DG serve as a unique local circuit component to regulate hippocampal neurogenesis [ 65 , 66 ]. Thus, reduced PV+ interneurons in DG result in the loss of adult-generated neurons in poly (I:C) offspring, which further causes an increase in gamma oscillation.…”

Section: Discussionmentioning

confidence: 99%

Modulating microglia activation prevents maternal immune activation induced schizophrenia-relevant behavior phenotypes via arginase 1 in the dentate gyrus

Xia

Zhang

Lin

et al. 2020

Neuropsychopharmacol.

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Prenatal infection during pregnancy increases the risk for developing neuropsychiatric disorders such as schizophrenia. This is linked to an inflammatory microglial phenotype in the offspring induced by maternal immune activation (MIA). Microglia are crucial for brain development and maintenance of neuronal niches, however, whether and how their activation is involved in the regulation of neurodevelopment remains unclear. Here, we used a MIA rodent model in which polyinosinic: polycytidylic acid (poly (I:C)) was injected into pregnant mice. We found fewer parvalbumin positive (PV+) cells and impaired GABAergic transmission in the dentate gyrus (DG), accompanied by schizophrenia-like behavior in the adult offspring. Minocycline, a potent inhibitor of microglia activation, successfully prevented the above-mentioned deficits in the offspring. Furthermore, by using microglia-specific arginase 1 (Arg1) ablation as well as overexpression in DG, we identified a critical role of Arg1 in microglia activation to protect against poly (I:C) imparted neuropathology and altered behavior in offspring. Taken together, our results highlight that Arg1-mediated alternative activation of microglia are potential therapeutic targets for psychiatric disorders induced by MIA.

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“…A recent study showed that pTau accumulates in the hippocampal subgranular cell zone and hilus in AD patients. Most of these pTau-positive cells have been identified as GABAergic interneurons by co-labeling with glutamate decarboxylase 67 (GAD67) in PV and SST neurons, further suggesting GABA inhibitory interneuron function is disturbed in AD ( Zheng et al, 2020 ). Compared with controls, GABA inhibitory interneurons and SST neurons in the brains of AD patients are abnormally reduced, along with the inhibitory neurotransmitters ( Bareggi et al, 1982 ; Zimmer et al, 1984 ; Grouselle et al, 1998 ; Bai et al, 2015 ; Shetty and Bates, 2016 ; Table 1 ).…”

Section: Targeting Increased Numbers Of Gaba Inhibitory Interneuronsmentioning

confidence: 99%

GABAergic Inhibitory Interneuron Deficits in Alzheimer’s Disease: Implications for Treatment

et al. 2020

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Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by severe cognitive deficits and pathologically by amyloid plaques, neuronal loss, and neurofibrillary tangles. Abnormal amyloid β-protein (Aβ) deposition in the brain is often thought of as a major initiating factor in AD neuropathology. However, gammaaminobutyric acid (GABA) inhibitory interneurons are resistant to Aβ deposition, and Aβ decreases synaptic glutamatergic transmission to decrease neural network activity. Furthermore, there is now evidence suggesting that neural network activity is aberrantly increased in AD patients and animal models due to functional deficits in and decreased activity of GABA inhibitory interneurons, contributing to cognitive deficits. Here we describe the roles played by excitatory neurons and GABA inhibitory interneurons in Aβ-induced cognitive deficits and how altered GABA interneurons regulate AD neuropathology. We also comprehensively review recent studies on how GABA interneurons and GABA receptors can be exploited for therapeutic benefit. GABA interneurons are an emerging therapeutic target in AD, with further clinical trials urgently warranted.

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Interneuron Accumulation of Phosphorylated tau Impairs Adult Hippocampal Neurogenesis by Suppressing GABAergic Transmission

Cited by 107 publications

References 74 publications

GSK-3β activation accelerates early-stage consumption of Hippocampal Neurogenesis in senescent mice

GSK-3β activation accelerates early-stage consumption of Hippocampal Neurogenesis in senescent mice

Modulating microglia activation prevents maternal immune activation induced schizophrenia-relevant behavior phenotypes via arginase 1 in the dentate gyrus

GABAergic Inhibitory Interneuron Deficits in Alzheimer’s Disease: Implications for Treatment

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