BackgroundExosomes, small extracellular vesicles of endosomal origin, have been suggested to be involved in both the metabolism and aggregation of Alzheimer’s disease (AD)-associated amyloid β-protein (Aβ). Despite their ubiquitous presence and the inclusion of components which can potentially interact with Aβ, the role of exosomes in regulating synaptic dysfunction induced by Aβ has not been explored.ResultsWe here provide in vivo evidence that exosomes derived from N2a cells or human cerebrospinal fluid can abrogate the synaptic-plasticity-disrupting activity of both synthetic and AD brain-derived Aβ. Mechanistically, this effect involves sequestration of synaptotoxic Aβ assemblies by exosomal surface proteins such as PrPC rather than Aβ proteolysis.ConclusionsThese data suggest that exosomes can counteract the inhibitory action of Aβ, which contributes to perpetual capability for synaptic plasticity.
Despite considerable evidence for a critical role of neuroligin-1 in the specification of excitatory synapses, the cellular mechanisms and physiological roles of neuroligin-1 in mature neural circuits are poorly understood. In mutant mice deficient in neuroligin-1, or adult rats in which neuroligin-1 was depleted, we have found that neuroligin-1 stabilizes the NMDA receptors residing in the postsynaptic membrane of amygdala principal neurons, which allows for a normal range of NMDA receptor-mediated synaptic transmission. We observed marked decreases in NMDA receptor-mediated synaptic currents at afferent inputs to the amygdala of neuroligin-1 knockout mice. However, the knockout mice exhibited a significant impairment in spike-timing-dependent long-term potentiation (STD-LTP) at the thalamic but not the cortical inputs to the amygdala. Subsequent electrophysiological analyses indicated that STD-LTP in the cortical pathway is largely independent of activation of postsynaptic NMDA receptors. These findings suggest that neuroligin-1 can modulate, in a pathway-specific manner, synaptic plasticity in the amygdala circuits of adult animals, likely by regulating the abundance of postsynaptic NMDA receptors.STD-LTP | thalamic pathway | cortical pathway | autism A number of studies have indicated that synaptically localized cell adhesion molecules not only trigger de novo synapse formation but also play a critical role in regulating both synaptic transmission and synaptic plasticity (1). The heterophilic cell adhesion molecules-neurexins and neuroligins-have emerged as important regulators of synaptic function in mature neural circuits (2). Among the several isoforms, neuroligin-1 (NLGN1) has been reported to be present in the postsynaptic density of excitatory synapses (3) and interacts with the postsynaptic scaffolding protein PSD-95 via a specific PDZ binding motif (4). We and others have shown that in the adult brain NLGN1 is critically involved in the maintenance of currents mediated by N-methyl-D-aspartic acid type glutamate receptors (NMDARs) but not by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid type glutamate receptors (AMPARs) (5, 6). Given the importance of NMDARs for synaptic plasticity and neuropathology (7,8), it seems particularly important to understand how NLGN1, a candidate gene in autism, controls NMDAR-mediated synaptic transmission.Certain forms of synaptic plasticity are regulated by NMDARs (9), and NLGN1 is expressed ubiquitously in various brain areas (2, 3). Thus, it is likely that NLGN1 expression regulates synaptic plasticity as well as the maturation and refinement of neural networks. Indeed, we have previously found that appropriate levels of NLGN1 are required for normal development of pairinginduced LTP at the auditory thalamic inputs to the lateral nucleus of the amygdala (LA) (6). In addition to the thalamic inputs, LA has another auditory input from the auditory cortex (10). Synaptic plasticity induced in the cortical pathway also contributes to the formation and consolidation ...
MicroRNAs (miRNAs) have recently come to be viewed as critical players that modulate a number of cellular features in various biological systems including the mature CNS by exerting regulatory control over the stability and translation of mRNAs. Despite considerable evidence for the regulatory functions of miRNAs, the identities of the miRNA species that are involved in the regulation of synaptic transmission and plasticity and the mechanisms by which these miRNAs exert functional roles remain largely unknown. In the present study, the expression of microRNA-188 (miR-188) was found to be upregulated by the induction of long-term potentiation (LTP). The protein level of neuropilin-2 (Nrp-2), one of the possible molecular targets for miR-188, was decreased during LTP induction. We also confirmed that the luciferase activity of the 3Ј-UTR of Nrp-2 was diminished by treatment with a miR-188 oligonucleotide but not with a scrambled miRNA oligonucleotide. Nrp-2 serves as a receptor for semaphorin 3F, which is a negative regulator of spine development and synaptic structure. In addition, miR-188 specifically rescued the reduction in dendritic spine density induced by Nrp-2 expression in hippocampal neurons from rat primary culture. Furthermore, miR-188 counteracted the decrease in the miniature EPSC frequency induced by Nrp-2 expression in hippocampal neurons from rat primary culture. These findings suggest that miR-188 serves to fine-tune synaptic plasticity by regulating Nrp-2 expression.
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