ATP11B deficiency leads to impairment of hippocampal synaptic plasticity

Abstract

Synaptic plasticity is known to regulate and support signal transduction between neurons, while synaptic dysfunction contributes to multiple neurological and other brain disorders; however, the specific mechanism underlying this process remains unclear. In the present study, abnormal neural and dendritic morphology was observed in the hippocampus following knockout of Atp11b both in vitro and in vivo. Moreover, ATP11B modified synaptic ultrastructure and promoted spine remodeling via the asymmetrical distribution of phosphatidylserine and enhancement of glutamate release, glutamate receptor expression, and intracellular Ca2+ concentration. Furthermore, experimental results also indicate that ATP11B regulated synaptic plasticity in hippocampal neurons through the MAPK14 signaling pathway. In conclusion, our data shed light on the possible mechanisms underlying the regulation of synaptic plasticity and lay the foundation for the exploration of proteins involved in signal transduction during this process.

Pathological Mechanisms Linking Diabetes Mellitus and Alzheimer’s Disease: the Receptor for Advanced Glycation End Products (RAGE)

“…Many studies have shown that increased phosphorylation of tau is closely related to the PI3K signaling pathway (Wang et al, 2018 , 2019 ; Wei et al, 2019 ; Zhao et al, 2019 ). Activation of the PI3K signaling pathway can reduce the over-phosphorylation of tau (Xiong et al, 2020 ).…”

“…Many studies have shown that increased phosphorylation of tau is closely related to the PI3K signaling pathway (Wang et al, , 2019Wei et al, 2019;Zhao et al, 2019).…”

An intrinsic endothelial dysfunction causes cerebral small vessel disease

“…ATP11A or C, or others). There is impairment of hippocampal synaptic plasticity in a global- Atp11b KO mouse, but other phenotypes were not described(42), and so conditional mutants will be needed to unpick the relative contributions of each cell type to each pathology. Our previous identification of a SNP in ATP11B associated with human SVD MR changes indicates that the suggested effect on membranes has human relevance, and worth further investigation.…”

Cerebral Vascular Dysfunctions Detected in Human Small Vessel Disease and Implications for Preclinical Studies

“…Extracellular vesicles from ECs and various blood cells attach to other cells via P-selectin glycoprotein ligand-1 and exposed phosphatidylserine (139), disruptions to which may increase platelet adhesion, hemostasis, and thrombosis, possibly contributing to vascular stasis and latestage thrombosis in SHRSPs and human SVD. ATP11B expression is not confined to cerebral ECs and blood cells but is relatively ubiquitous (https://www.proteinatlas.org/ENSG00000058063-ATP11B), with potential for compensation by other family members ATP11A and C. A neural phenotype for loss of ATP11B as in the SHRSP also occurs in a transgenic mouse with global Atp11b knockout, which showed abnormal neural, dendritic, and synapse morphology in the hippocampus, with altered distribution of membrane phosphatidylserine and downstream effects on glutamate release, glutamate receptor expression, and intracellular Ca 2+ concentration, possibly through the MAPK14 signaling pathway (140). The MAPK14 pathway is linked with cAMP response element-binding protein, a component of the dysregulated inflammatory pathways in the SHRSP (125), although it is not known if a similar effect occurs on SHRSP synapses.…”