miR-181a negatively modulates synaptic plasticity in hippocampal cultures and its inhibition rescues memory deficits in a mouse model of Alzheimer's disease.

MicroRNAs play a pivotal role in rapid, dynamic, and spatiotemporal modulation of synaptic functions. Among them, recent emerging evidence highlights that microRNA-181a (miR-181a) is particularly abundant in hippocampal neurons and controls the expression of key plasticity-related proteins at synapses. We have previously demonstrated that miR-181a was upregulated in the hippocampus of a mouse model of Alzheimer's disease (AD) and correlated with reduced levels of plasticity-related proteins. Here, we further investigated the underlying mechanisms by which miR-181a negatively modulated synaptic plasticity and memory. In primary hippocampal cultures, we found that an activity-dependent upregulation of the microRNA-regulating protein, translin, correlated with reduction of miR-181a upon chemical long-term potentiation (cLTP), which induced upregulation of GluA2, a predicted target for miR-181a, and other plasticity-related proteins. Additionally, Aβ treatment inhibited cLTP-dependent induction of translin and subsequent reduction of miR-181a, and cotreatment with miR-181a antagomir effectively reversed the effects elicited by Aβ but did not rescue translin levels, suggesting that the activity-dependent upregulation of translin was upstream of miR-181a. In mice, a learning episode markedly decreased miR-181a in the hippocampus and raised the protein levels of GluA2. Lastly, we observed that inhibition of miR-181a alleviated memory deficits and increased GluA2 and GluA1 levels, without restoring translin, in the 3xTg-AD model. Taken together, our results indicate that miR-181a is a major negative regulator of the cellular events that underlie synaptic plasticity and memory through AMPA receptors, and importantly, Aβ disrupts this process by suppressing translin and leads to synaptic dysfunction and memory impairments in AD.

Rodriguez-Ortiz CJ ，Prieto GA ，Martini AC ，Forner S ，Trujillo-Estrada L ，LaFerla FM ，Baglietto-Vargas D ，Cotman CW ，Kitazawa M ... -  《-》

TRPV1 activation alleviates cognitive and synaptic plasticity impairments through inhibiting AMPAR endocytosis in APP23/PS45 mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is one of the most common causes of neurodegenerative diseases in the elderly. The accumulation of amyloid-β (Aβ) peptides is one of the pathological hallmarks of AD and leads to the impairments of synaptic plasticity and cognitive function. The transient receptor potential vanilloid 1 (TRPV1), a nonselective cation channel, is involved in synaptic plasticity and memory. However, the role of TRPV1 in AD pathogenesis remains largely elusive. Here, we reported that the expression of TRPV1 was decreased in the brain of APP23/PS45 double transgenic AD model mice. Genetic upregulation of TRPV1 by adeno-associated virus (AAV) inhibited the APP processing and Aβ deposition in AD model mice. Meanwhile, upregulation of TRPV1 ameliorated the deficits of hippocampal CA1 long-term potentiation (LTP) and spatial learning and memory through inhibiting GluA2-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) endocytosis. Furthermore, pharmacological activation of TRPV1 by capsaicin (1 mg/kg, i.p.), an agonist of TRPV1, dramatically reversed the impairments of hippocampal CA1 LTP and spatial learning and memory in AD model mice. Taken together, these results indicate that TRPV1 activation effectively ameliorates cognitive and synaptic functions through inhibiting AMPAR endocytosis in AD model mice and could be a novel molecule for AD treatment.

Du Y ，Fu M ，Huang Z ，Tian X ，Li J ，Pang Y ，Song W ，Tian Wang Y ，Dong Z ... -  《-》

miR-369-5p Positively Modulates Plasticity-Related Proteins in Hippocampal Cultures and in a Mouse Model of Alzheimer's Disease.

Liu Y ，Xiang Q 《-》

Dopamine-regulated microRNA MiR-181a controls GluA2 surface expression in hippocampal neurons.

Saba R ，Störchel PH ，Aksoy-Aksel A ，Kepura F ，Lippi G ，Plant TD ，Schratt GM ... -  《-》

REDD1 Is Involved in Amyloid β-Induced Synaptic Dysfunction and Memory Impairment.

Yi JH ，Kwon H ，Cho E ，Jeon J ，Lee J ，Lee YC ，Cho JH ，Jun M ，Moon M ，Ryu JH ，Kim JS ，Choi JW ，Park SJ ，Lee S ，Kim DH ... -  《-》