Type VI adenylyl cyclase negatively regulates GluN2B-mediated LTD and spatial reversal learning

Chang, Ching-Pang; Lee, Cheng Ta; Hou, Wen Hsien; Lin, Meng Syuan; Lai, Hsing Lin; Chien, Chen Li; Chang, Chen; Cheng, Pei‐Lin; Lien, Cheng Chang; Chern, Yijuang

doi:10.1038/srep22529

Cited by 9 publications

(6 citation statements)

References 57 publications

(93 reference statements)

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“… 17 The increased level of D1R on the membrane facilitates the CREB pathway, 51 which is required for long‐term synaptic plasticity and memory consolidation. 47 Activation of the CREB pathway can enhance the expression of GluN2B, 52 which is important for plasticity at the postsynaptic density. 46 Our results show that knockout Gm527 in D1R‐positive neurons can increase D1R on the plasma membrane, leading to activation of the CREB pathway in glutamatergic neurons and long‐term plasticity in the DG (Figure 4 ).…”

Section: Discussionmentioning

confidence: 99%

Gm527 deficiency in dentate gyrus improves memory through upregulating dopamine D1 receptor pathway

et al. 2023

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AimsDopamine D1 receptor (D1R) hypofunction is associated with negative and cognitive symptoms in schizophrenia; therefore, the mechanism of D1R function modulation needs further investigation. Gm527 is the rodent homologous of the schizophrenia‐related gene C14orf28, encoding a predicated D1R‐interacting protein. However, the role of Gm527‐D1R interaction in schizophrenia needs to be clarified.MethodsGm527‐floxed mice were generated and crossed with D1‐Cre mice (D1:Gm527−/−) to knockout Gm527 in D1R‐positive neurons. Then behavioral tests were performed to explore the schizophrenia‐related phenotypes. Immunofluorescence, fluorescence in situ hybridization, electrophysiological recording, quantitative real‐time PCR, and western blotting were conducted to investigate the mechanisms.ResultsWorking memory, long‐term memories, and adult neurogenesis in the DG were enhanced in D1:Gm527−/− mice. LTP was also increased in the DG in D1:Gm527−/− mice, resulting from the Gm527 knockout‐induced D1R expression enhancement on the plasma membrane and subsequently cAMP signaling and NMDA receptor pathways activation. The requirement of Gm527 knockout in the DG was confirmed by reversing Gm527 expression or knockdown Gm527 in the DG D1R‐positive neurons through AAV‐CAG‐FLEX‐Gm527‐GFP or AAV‐CMV‐FLEX‐EGFP‐Gm527‐RNAi injection.ConclusionsThe DG Gm527 knockout induces D1R hyperfunction in improving schizophrenia cognitive symptoms.

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Section: Discussionmentioning

confidence: 99%

Gm527 deficiency in dentate gyrus improves memory through upregulating dopamine D1 receptor pathway

et al. 2023

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“…Spatial memory and cognitive flexibility of mice aged 10–11 months were evaluated using the Morris water maze test as described with slight modifications [ 36 ]. A circular swimming pool (154 cm in diameter, 51 cm in height) was filled with milky water (30 cm in depth, kept at 20 °C), and divided into four quadrants (T: target; L: target left; R: target right; O: opposite) with distinct visual cues on the tank wall of each quadrant.…”

Section: Methodsmentioning

confidence: 99%

Equilibrative nucleoside transporter 1 inhibition rescues energy dysfunction and pathology in a model of tauopathy

Chang

Chuang

et al. 2021

acta neuropathol commun

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Tau pathology is instrumental in the gradual loss of neuronal functions and cognitive decline in tauopathies, including Alzheimer’s disease (AD). Earlier reports showed that adenosine metabolism is abnormal in the brain of AD patients while consequences remained ill-defined. Herein, we aimed at investigating whether manipulation of adenosine tone would impact Tau pathology, associated molecular alterations and subsequent neurodegeneration. We demonstrated that treatment with an inhibitor (J4) of equilibrative nucleoside transporter 1 (ENT1) exerted beneficial effects in a mouse model of Tauopathy. Treatment with J4 not only reduced Tau hyperphosphorylation but also rescued memory deficits, mitochondrial dysfunction, synaptic loss, and abnormal expression of immune-related gene signatures. These beneficial effects were particularly ascribed to the ability of J4 to suppress the overactivation of AMPK (an energy reduction sensor), suggesting that normalization of energy dysfunction mitigates neuronal dysfunctions in Tauopathy. Collectively, these data highlight that targeting adenosine metabolism is a novel strategy for tauopathies.

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“…Primary hippocampal neurons were prepared as described previously [35]. Cells were maintained under 5% CO 2 for 14 days and subjected to the indicated treatments.…”

Section: Methodsmentioning

confidence: 99%

GSK3β negatively regulates TRAX, a scaffold protein implicated in mental disorders, for NHEJ-mediated DNA repair in neurons

et al. 2018

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Translin-associated protein X (TRAX) is a scaffold protein with various functions and has been associated with mental illnesses, including schizophrenia. We have previously demonstrated that TRAX interacts with a Gsα protein-coupled receptor, the A 2A adenosine receptor (A 2A R), and mediates the function of this receptor in neuritogenesis. In addition, stimulation of the A 2A R markedly ameliorates DNA damage evoked by elevated oxidative stress in neurons derived from induced pluripotent stem cells (iPSCs). Here, we report that glycogen synthase kinase 3 beta (GSK3β) and disrupted-inschizophrenia 1 (DISC1) are two novel interacting proteins of TRAX. We present evidence to suggest that the stimulation of A 2A R markedly facilitated DNA repair through the TRAX/DISC1/GSK3β complex in a rat neuronal cell line (PC12), primary mouse neurons, and human medium spiny neurons derived from iPSCs. A 2A R stimulation led to the inhibition of GSK3β, thus dissociating the TRAX/DISC1/GSK3β complex and facilitating the non-homologous end-joining pathway (NHEJ) by enhancing the activation of a DNA-dependent protein kinase via phosphorylation at Thr 2609 . Similarly, pharmacological inhibition of GSK3β by SB216763 also facilitated the TRAX-mediated repair of oxidative DNA damage. Collectively, GSK3β binds with TRAX and negatively affects its ability to facilitate NHEJ repair. The suppression of GSK3β by A 2A R activation or a GSK3β inhibitor releases TRAX for the repair of oxidative DNA damage. Our findings shed new light on the molecular mechanisms underlying diseases associated with DNA damage and provides a novel target (i.e., the TRAX/DISC1/GSK3β complex) for future therapeutic development for mental disorders.

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Type VI adenylyl cyclase negatively regulates GluN2B-mediated LTD and spatial reversal learning

Cited by 9 publications

References 57 publications

Gm527 deficiency in dentate gyrus improves memory through upregulating dopamine D1 receptor pathway

Gm527 deficiency in dentate gyrus improves memory through upregulating dopamine D1 receptor pathway

Equilibrative nucleoside transporter 1 inhibition rescues energy dysfunction and pathology in a model of tauopathy

GSK3β negatively regulates TRAX, a scaffold protein implicated in mental disorders, for NHEJ-mediated DNA repair in neurons

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