Postsynaptic Terminal Research Articles

Exogenous Alpha-Synuclein Alters Pre- and Post-Synaptic Activity by Fragmenting Lipid Rafts

Alpha-synuclein (αSyn) interferes with multiple steps of synaptic activity at pre-and post-synaptic terminals, however the mechanism/s by which αSyn alters neurotransmitter release and synaptic potentiation is unclear. By atomic force microscopy we show that human αSyn, when incubated with reconstituted membrane bilayer, induces lipid rafts' fragmentation. As a consequence, ion channels and receptors are displaced from lipid rafts with consequent changes in their activity. The enhanced calcium entry leads to acute mobilization of synaptic vesicles, and exhaustion of neurotransmission at later stages. At the post-synaptic terminal, an acute increase in glutamatergic transmission, with increased density of PSD-95 puncta, is followed by disruption of the interaction between N-methyl-d-aspartate receptor (NMDAR) and PSD-95 with ensuing decrease of long term potentiation. While cholesterol loading prevents the acute effect of αSyn at the presynapse; inhibition of casein kinase 2, which appears activated by reduction of cholesterol, restores the correct localization and clustering of NMDARs.

Extending computational models of astrocyte-neuron interactions with biochemical mechanisms on the postsynaptic terminal

There is increasing evidence that astrocytes not only interact with each other but also with adjacent neurons in the neural circuitry in a variety of brain areas. Many biophysical and biochemical mechanisms have been proposed to explain these interactions in vitro. Based on the experimental literature, the mechanisms involved seem to depend not only on the developmental stage of an animal but also on the brain area, neural circuitry, as well as on the experimental technique used to characterize the phenomena. Using biophysically and biochemically detailed compartmental models, we are interested in understanding how these interactions between neurons and astrocytes may regulate information processing and, notably, different forms of synaptic plasticity [1]. In this study, we designed a new model of the so-called tripartite synapse. The tripartite synapse is a concept of synaptic physiology in which there are three parts of a synapse: the presynaptic and postsynaptic terminals, and an astrocyte in between them [2]. Many previous studies in vitro have shown that gliotransmitters like glutamate are released from astrocytes into the synaptic cleft following activation of presynaptic or postsynaptic terminals, or activation of the astrocyte itself [3]. However, none of the previous modeling studies incorporate all features necessary to understand the complex interactions in full detail. We extend beyond these previously published fundamental, yet relatively simplistic representations (see, e.g., [4]). We describe the postsynaptic terminal using a two-compartmental approach, in addition to the presynaptic terminal and the astrocyte. We specifically address the postsynaptic mechanisms and their role in activating astrocytic calcium signaling and subsequent gliotransmission. By introducing realistic model components on the postsynaptic terminal, such as voltage-dependent receptor channels and the G-protein activated signaling cascades, we observe stimulus-dependent changes in astrocyte calcium oscillations leading to activation of not only astrocytes, but also of adjacent neurons. The long-term goal of our work is to develop detailed models of astrocyte-neuron interactions for different brain areas which allow testing experimentally evoked hypothesis, as well as some controversies in the field (see, e.g., [5]). These models will open up new avenues to assess the effects of numerous mechanisms of astrocytes on the dynamics of local neuronal networks. Only through systematic integration of in vitro and in silico work will we be able to understand how astrocytes may contribute to brain information processing and plasticity.

Evolution of Synapse Complexity and Diversity

Proteomic studies of the composition of mammalian synapses have revealed a high degree of complexity. The postsynaptic and presynaptic terminals are molecular systems with highly organized protein networks producing emergent physiological and behavioral properties. The major classes of synapse proteins and their respective functions in intercellular communication and adaptive responses evolved in prokaryotes and eukaryotes prior to the origins of neurons in metazoa. In eukaryotes, the organization of individual proteins into multiprotein complexes comprising scaffold proteins, receptors, and signaling enzymes formed the precursor to the core adaptive machinery of the metazoan postsynaptic terminal. Multiplicative increases in the complexity of this protosynapse machinery secondary to genome duplications drove synaptic, neuronal, and behavioral novelty in vertebrates. Natural selection has constrained diversification in mammalian postsynaptic mechanisms and the repertoire of adaptive and innate behaviors. The evolution and organization of synapse proteomes underlie the origins and complexity of nervous systems and behavior.

Dynamical Mean Field Model of a Neural-Glial Mass

Our goal is to model the behavior of an ensemble of interacting neurons and astrocytes (the neural-glial mass). For this, a model describing N tripartite synapses is proposed. Each tripartite synapse consists of presynaptic and postsynaptic nerve terminals, as well as the synaptically associated astrocytic microdomain, and is described by a system of 13 stochastic differential equations. Then, by applying the dynamical mean field approximation (DMA) (Hasegawa, 2003a , 2003b ) the system of 13N equations is reduced to 13(13 + 2) = 195 deterministic differential equations for the means and the second-order moments of local and global variables. Simulations are carried out for studying the response of the neural-glial mass to external inputs applied to either the presynaptic terminals or the astrocytes. Three cases were considered: the astrocytes influence only the presynaptic terminal, only the postsynaptic terminal, or both the presynaptic and postsynaptic terminals. As a result, a wide range of responses varying from singles spikes to train of spikes was evoked on presynaptic and postsynaptic terminals. The experimentally observed phenomenon of spontaneous activity in astrocytes was replicated on the neural-glial mass. The model predicts that astrocytes can have a strong and activity-dependent influence on synaptic transmission. Finally, simulations show that the dynamics of astrocytes influences the synchronization ratio between neurons, predicting a peak in the synchronization for specific values of the astrocytes' parameters.

P3-441: Expression of mRNAs regulating local translation in synaptic terminals of MCI and early ad brain

Recent evidence suggests Alzheimer's Disease (AD) begins with subtle alterations of synaptic function producing memory deficits prior to histopathological changes. Decreased expression of presynaptic proteins before synapse loss is part of a continuum of modifications during clinical progression of dementia. However, activity–dependant expression of proteins locally translated in both pre–and post–synaptic terminals, and mRNA binding proteins regulating their translation, have not been assessed in the AD brain. Perturbation of synaptic protein synthesis could result from modifications in structure and function of the pre–synaptic terminal and/or direct effects of Ab peptides at the post–synaptic terminal. To compare expression of mRNAs locally translated at the synapse in MCI/early AD versus controls. Patients were grouped primarily according to MMSE but also adjusted for amyloid burden. Frontal cortex (Area 9) was obtained post–mortem, from 8 age–matched controls, 6 MCI/early AD and 10 moderate–to–severe AD patients. Synaptoneurosomes were prepared and mRNA extracted for Affymetrix microarray profiling and quantitative PCR. Clustering of genes and fold change data was prepared with the Bioconductor package. Gene annotation and gene ontology groupings were identified using EASE (http://david.niaid.nih.gov/david/ease.htm). We screened mRNA sequences of changed genes for 3∼ UTR regulatory motifs, such as the cytoplasmic polyadenylation element (CPE), which regulate local translation at the synapse. In MCI there is up–regulation of genes involved in synaptic transmission, transport (including vesicle–mediated transport) and cell recognition, and down–regulation of cell–cycle genes, (p<0.01). Approximately 50% of up–regulated genes code for proteins localized to the membrane. We found 50 putative CPE–containing mRNAs out of 304 up–regulated (16%) and 22 of 157 down–regulated (14%). Genes encoding the mRNA–binding proteins pumilio homolog and HuD, and some corresponding mRNAs they regulate, were also up–regulated in MCI. Synaptoneurosome samples were evaluated for in vitro translation using biotin–labeled tRNA. Immunoblots revealed biotin labeled aCAMKII in all synaptosomal preparations tested. Thus, using human synaptoneurosomes, we have enriched a group of mRNAs with regulatory sequences involved in de novo protein synthesis at the synapse. Microarray profiling reveals that some of these genes are impacted in MCI brain and may be implicated in functional impairment during AD progression.

Synaptic alterations in the acoustic cortex of the rat following insulin-induced hypoglycemia.

Hypoglycemia was induced by intracarotid insulin infusions in adult Lewis rats. Electron microscopy of the acoustic cortices in these animals revealed that hypoglycemia provoked marked morphological and morphometric alterations in the pre- and postsynaptic terminals present, as well as in the astrocytic processes seen. The number of the synaptic vesicles in the "active zone" of the synapses was dramatically decreased, with most of the vesicles loosely dispersed in the entire presynaptic profile. Some of the pre- and postsynaptic terminals were enlarged and contained dilated cisternae of smooth endoplasmic reticulum, as well as mitochondria exhibiting a marked internal disorganization. The synaptic clefts in a large number of synapses were dilated and contained fibrillary material. The most striking morphological alterations seen involved a membrane discontinuity of the postsynaptic terminal and was found mostly in the synapses of the superficial layer of the acoustic cortex. Most of the morphological alterations observed in the acoustic cortex following uncomplicated hypoglycemia are seen in sensitive areas of the brain after ischemia or hypoxia.