Amyloid pathology disrupts gliotransmitter release in astrocytes.

Accumulation of amyloid-beta (Aß) is associated with synaptic dysfunction and destabilization of astrocytic calcium homeostasis. A growing body of evidence support astrocytes as active modulators of synaptic transmission via calcium-mediated gliotransmission. However, the details of mechanisms linking Aß signaling, astrocytic calcium dynamics, and gliotransmission are not known. We developed a biophysical model that describes calcium signaling and the ensuing gliotransmitter release from a single astrocytic process when stimulated by glutamate release from hippocampal neurons. The model accurately captures the temporal dynamics of microdomain calcium signaling and glutamate release via both kiss-and-run and full-fusion exocytosis. We investigate the roles of two crucial calcium regulating machineries affected by Aß: plasma-membrane calcium pumps (PMCA) and metabotropic glutamate receptors (mGluRs). When we implemented these Aß-affected molecular changes in our astrocyte model, it led to an increase in the rate and synchrony of calcium events. Our model also reproduces several previous findings of Aß associated aberrant calcium activity, such as increased intracellular calcium level and increased spontaneous calcium activity, and synchronous calcium events. The study establishes a causal link between previous observations of hyperactive astrocytes in Alzheimer's disease (AD) and Aß-induced modifications in mGluR and PMCA functions. Analogous to neurotransmitter release, gliotransmitter exocytosis closely tracks calcium changes in astrocyte processes, thereby guaranteeing tight control of synaptic signaling by astrocytes. However, the downstream effects of AD-related calcium changes in astrocytes on gliotransmitter release are not known. Our results show that enhanced rate of exocytosis resulting from modified calcium signaling in astrocytes leads to a rapid depletion of docked vesicles that disrupts the crucial temporal correspondence between a calcium event and vesicular release. We propose that the loss of temporal correspondence between calcium events and gliotransmission in astrocytes pathologically alters astrocytic modulation of synaptic transmission in the presence of Aß accumulation.

Intracellular calcium stores mediate metaplasticity at hippocampal dendritic spines.

KEY POINTS: Calcium (Ca2+ ) entry mediated by NMDA receptors is considered central to the induction of activity-dependent synaptic plasticity in hippocampal area CA1; this description does not, however, take into account the potential contribution of endoplasmic reticulum (ER) Ca2+ stores. The ER has a heterogeneous distribution in CA1 dendritic spines, and may introduce localized functional differences in Ca2+ signalling between synapses, as suggested by experiments on metabotropic receptor-dependent long-term depression. A physiologically detailed computational model of Ca2+ dynamics at a CA3-CA1 excitatory synapse characterizes the contribution of spine ER via metabotropic signalling during plasticity induction protocols. ER Ca2+ release via IP3 receptors modulates NMDA receptor-dependent plasticity in a graded manner, to selectively promote synaptic depression with relatively diminished effect on LTP induction; this may temper further strengthening at the stronger synapses which are preferentially associated with ER-containing spines. Acquisition of spine ER may thus represent a local, biophysically plausible 'metaplastic switch' at potentiated CA1 synapses, contributing to the plasticity-stability balance in neural circuits. ABSTRACT: Long-term plasticity mediated by NMDA receptors supports input-specific, Hebbian forms of learning at excitatory CA3-CA1 connections in the hippocampus. There exists an additional layer of stabilizing mechanisms that act globally as well as locally over multiple time scales to ensure that plasticity occurs in a constrained manner. Here, we investigated the role of calcium (Ca2+ ) stores associated with the endoplasmic reticulum (ER) in the local regulation of plasticity at individual CA1 synapses. Our study was spurred by (1) the curious observation that ER is sparsely distributed in dendritic spines, but over-represented in larger spines that are likely to have undergone activity-dependent strengthening, and (2) evidence suggesting that ER motility at synapses can be rapid, and accompany activity-regulated spine remodelling. We constructed a physiologically realistic computational model of an ER-bearing CA1 spine, and examined how IP3 -sensitive Ca2+ stores affect spine Ca2+ dynamics during activity patterns mimicking the induction of long-term potentiation and long-term depression (LTD). Our results suggest that the presence of ER modulates NMDA receptor-dependent plasticity in a graded manner that selectively enhances LTD induction. We propose that ER may locally tune Ca2+ -based plasticity, providing a braking mechanism to mitigate runaway strengthening at potentiated synapses. Our study provides a biophysically accurate description of postsynaptic Ca2+ regulation, and suggests that ER in the spine may promote the re-use of hippocampal synapses with saturated strengths.

Short-term plasticity constrains spatial organization of a hippocampal presynaptic terminal.

Although the CA3-CA1 synapse is critically important for learning and memory, experimental limitations have to date prevented direct determination of the structural features that determine the response plasticity. Specifically, the local calcium influx responsible for vesicular release and short-term synaptic facilitation strongly depends on the distance between the voltage-dependent calcium channels (VDCCs) and the presynaptic active zone. Estimates for this distance range over two orders of magnitude. Here, we use a biophysically detailed computational model of the presynaptic bouton and demonstrate that available experimental data provide sufficient constraints to uniquely reconstruct the presynaptic architecture. We predict that for a typical CA3-CA1 synapse, there are ~70 VDCCs located 300 nm from the active zone. This result is surprising, because structural studies on other synapses in the hippocampus report much tighter spatial coupling. We demonstrate that the unusual structure of this synapse reflects its functional role in short-term plasticity (STP).

Modelling vesicular release at hippocampal synapses.

We study local calcium dynamics leading to a vesicle fusion in a stochastic, and spatially explicit, biophysical model of the CA3-CA1 presynaptic bouton. The kinetic model for vesicle release has two calcium sensors, a sensor for fast synchronous release that lasts a few tens of milliseconds and a separate sensor for slow asynchronous release that lasts a few hundred milliseconds. A wide range of data can be accounted for consistently only when a refractory period lasting a few milliseconds between releases is included. The inclusion of a second sensor for asynchronous release with a slow unbinding site, and thereby a long memory, affects short-term plasticity by facilitating release. Our simulations also reveal a third time scale of vesicle release that is correlated with the stimulus and is distinct from the fast and the slow releases. In these detailed Monte Carlo simulations all three time scales of vesicle release are insensitive to the spatial details of the synaptic ultrastructure. Furthermore, our simulations allow us to identify features of synaptic transmission that are universal and those that are modulated by structure.

Presynaptic endoplasmic reticulum regulates short-term plasticity in hippocampal synapses.

Short-term plasticity preserves a brief history of synaptic activity that is communicated to the postsynaptic neuron. This is primarily regulated by a calcium signal initiated by voltage dependent calcium channels in the presynaptic terminal. Imaging studies of CA3-CA1 synapses reveal the presence of another source of calcium, the endoplasmic reticulum (ER) in all presynaptic terminals. However, the precise role of the ER in modifying STP remains unexplored. We performed in-silico experiments in synaptic geometries based on reconstructions of the rat CA3-CA1 synapses to investigate the contribution of ER. Our model predicts that presynaptic ER is critical in generating the observed short-term plasticity profile of CA3-CA1 synapses and allows synapses with low release probability to operate more reliably. Blocking the ER lowers facilitation in a manner similar to what has been previously characterized in animal models of Alzheimer's disease and underscores the important role played by presynaptic stores in normal function.

Alteration in synaptic nanoscale organization dictates amyloidogenic processing in Alzheimer's disease.

Despite intuitive insights into differential proteolysis of amyloid precursor protein (APP), the stochasticity behind local product formation through amyloidogenic pathway at individual synapses remain unclear. Here, we show that the major components of amyloidogenic machinery namely, APP and secretases are discretely organized into nanodomains of high local concentration compared to their immediate environment in functional zones of the synapse. Additionally, with the aid of multiple models of Alzheimer's disease (AD), we confirm that this discrete nanoscale chemical map of amyloidogenic machinery is altered at excitatory synapses. Furthermore, we provide realistic models of amyloidogenic processing in unitary vesicles originating from the endocytic zone of excitatory synapses. Thus, we show how an alteration in the stochasticity of synaptic nanoscale organization contributes to the dynamic range of C-terminal fragments ß (CTFß) production, defining the heterogeneity of amyloidogenic processing at individual synapses, leading to long-term synaptic deficits as seen in AD.

A comparison of deterministic and stochastic simulations of neuronal vesicle release models.

We study the calcium-induced vesicle release into the synaptic cleft using a deterministic algorithm and MCell, a Monte Carlo algorithm that tracks individual molecules. We compare the average vesicle release probability obtained using both algorithms and investigate the effect of the three main sources of noise: diffusion, sensor kinetics and fluctuations from the voltage-dependent calcium channels (VDCCs). We find that the stochastic opening kinetics of the VDCCs are the main contributors to differences in the release probability. Our results show that the deterministic calculations lead to reliable results, with an error of less than 20%, when the sensor is located at least 50 nm from the VDCCs, corresponding to microdomain signaling. For smaller distances, i.e. nanodomain signaling, the error becomes larger and a stochastic algorithm is necessary.

Local Design Principles at Hippocampal Synapses Revealed by an Energy-Information Trade-Off.

Synapses across different brain regions display distinct structure-function relationships. We investigated the interplay of fundamental design constraints that shape the transmission properties of the excitatory CA3-CA1 pyramidal cell connection, a prototypic synapse for studying the mechanisms of learning in the mammalian hippocampus. This small synapse is characterized by probabilistic release of transmitter, which is markedly facilitated in response to naturally occurring trains of action potentials. Based on a physiologically motivated computational model of the rat CA3 presynaptic terminal, we show how unreliability and short-term dynamics of vesicular release work together to regulate the trade-off of information transfer versus energy use. We propose that individual CA3-CA1 synapses are designed to operate near the maximum possible capacity of information transmission in an efficient manner. Experimental measurements reveal a wide range of vesicular release probabilities at hippocampal synapses, which may be a necessary consequence of long-term plasticity and homeostatic mechanisms that manifest as presynaptic modifications of the release probability. We show that the timescales and magnitude of short-term plasticity (STP) render synaptic information transfer nearly independent of differences in release probability. Thus, individual synapses transmit optimally while maintaining a heterogeneous distribution of presynaptic strengths indicative of synaptically-encoded memory representations. Our results support the view that organizing principles that are evident on higher scales of neural organization percolate down to the design of an individual synapse.

Biophysical Basis of Alpha Rhythm Disruption in Alzheimer's Disease.

Occipital alpha is a prominent rhythm (∼10 Hz) detected in electroencephalography (EEG) during wakeful relaxation with closed eyes. The rhythm is generated by a subclass of thalamic pacemaker cells that burst at the alpha frequency, orchestrated by the interplay of hyperpolarization-activated cyclic nucleotide-gated channels (HCN) and calcium channels in response to elevated levels of ambient acetylcholine (ACh). These oscillations are known to have a lower peak frequency and coherence in the early stages of Alzheimer's disease (AD). Interestingly, calcium signaling, HCN channel expression and ACh signaling, crucial for orchestrating the alpha rhythm, are also known to be aberrational in AD. In a biophysically detailed network model of the thalamic circuit, we investigate the changes in molecular signaling and the causal relationships between them that lead to a disrupted thalamic alpha in AD. Our simulations show that lowered HCN expression leads to a slower thalamic alpha, which can be rescued by increasing ACh levels, a common therapeutic target of AD drugs. However, this rescue is possible only over a limited range of reduced HCN expression. The model predicts that lowered HCN expression can modify the network activity in the thalamic circuit leading to increased GABA release in the thalamus and disrupt the calcium homeostasis. The changes in calcium signaling make the network more susceptible to noise, causing a loss in rhythmic activity. Based on our results, we propose that reduced frequency and coherence of the occipital alpha rhythm seen in AD may result from downregulated HCN expression, rather than modified cholinergic signaling.

Real-time nanoscale organization of amyloid precursor protein.

Despite an intuitive understanding of the role of APP in health and disease, there exist few attempts to dissect its molecular localization at excitatory synapses. Though the biochemistry involved in the enzymatic processing of APP is well understood, there is a void in understanding the nonuniformity of the product formation in vivo. Here, we employed multiple paradigms of single molecules and ensemble based nanoscopic imaging to reveal that APP molecules are organized into regulatory nanodomains that are differentially compartmentalized in the functional zones of an excitatory synapse. Furthermore, with the aid of high density single particle tracking, we show that the lateral diffusion of APP in live cells dictates an equilibrium between these nanodomains and their nano-environment, which is affected in a detrimental variant of APP. Additionally, we incorporate this spatio-temporal detail 'in silico' to generate a realistic nanoscale topography of APP in dendrites and synapses. This approach uncovers a nanoscale heterogeneity in the molecular organization of APP, depicting a locus for differential APP processing. This holistic paradigm, to decipher the real-time heterogeneity of the substrate molecules on the nanoscale, could enable us to better evaluate the molecular constraints overcoming the ensemble approaches used traditionally to understand the kinetics of product formation.

Astrocytes optimize the synaptic transmission of information.

Chemical synapses transmit information via the release of neurotransmitter-filled vesicles from the presynaptic terminal. Using computational modeling, we predict that the limited availability of neurotransmitter resources in combination with the spontaneous release of vesicles limits the maximum degree of enhancement of synaptic transmission. This gives rise to an optimal tuning that depends on the number of active zones. There is strong experimental evidence that astrocytes that enwrap synapses can modulate the probabilities of vesicle release through bidirectional signaling and hence regulate synaptic transmission. For low-fidelity hippocampal synapses, which typically have only one or two active zones, the predicted optimal values lie close to those determined by experimentally measured astrocytic feedback, suggesting that astrocytes optimize synaptic transmission of information.

Modeling synaptic transmission of the tripartite synapse.

The tripartite synapse denotes the junction of a pre- and postsynaptic neuron modulated by a synaptic astrocyte. Enhanced transmission probability and frequency of the postsynaptic current-events are among the significant effects of the astrocyte on the synapse as experimentally characterized by several groups. In this paper we provide a mathematical framework for the relevant synaptic interactions between neurons and astrocytes that can account quantitatively for both the astrocytic effects on the synaptic transmission and the spontaneous postsynaptic events. Inferred from experiments, the model assumes that glutamate released by the astrocytes in response to synaptic activity regulates store-operated calcium in the presynaptic terminal. This source of calcium is distinct from voltage-gated calcium influx and accounts for the long timescale of facilitation at the synapse seen in correlation with calcium activity in the astrocytes. Our model predicts the inter-event interval distribution of spontaneous current activity mediated by a synaptic astrocyte and provides an additional insight into a novel mechanism for plasticity in which a low fidelity synapse gets transformed into a high fidelity synapse via astrocytic coupling.

Synaptic inhibition and pathologic hyperexcitability through enhanced neuron-astrocyte interaction: a modeling study.

Recently, upregulation of metabotropic glutamate receptors (mGluRs) on hippocampal astrocytes in epileptic tissues has become part of the etiology of epilepsy and suggests the involvement of astrocytes in the disease. Through computational modeling, we have shown in previous work that upregulated mGluRs on astrocytes can give rise to positive feedback in closed loop neuron-astrocyte circuits with epilepsy-type spontaneous neuronal spiking. In this paper we further quantify the necessary degree of upregulation of astrocytic mGluRs, relate it to recent clinical and experimental studies, and address through computational modeling the role of synaptic inhibition through interneurons in this form of hyperexcitability. We conclude that inhibitive circuitry cannot tame this form of hyperexcitability.

Dressed neurons: modeling neural-glial interactions.

Based on recent experimental data, we design a model for neuronal membrane potentials that incorporates the influence of the surrounding glia (dressed neurons). A neurotransmitter released into the synaptic cleft triggers a Ca(2+) response in nearby glial cells that spreads as a Ca(2+) wave and interacts with other synapses via the release of glutamate from astrocytes. We consider the simple case of a neuron-glia circuit that consists of a single neuron that triggers a Ca(2+) response in the glial cell which in turn feeds back into synapses of the same neuron. It is shown that persistent spiking can occur if the glutamate receptors on the astrocytes are overexpressed--a condition that has been reported from patients suffering from mesial-lobe epilepsy.

Spontaneous oscillations of dressed neurons: a new mechanism for epilepsy?

Most modeling studies of neurons and neuronal networks are based on the assumption that the neurons are isolated from their normal environment. Based on recent experimental data we put forward a model for neurons that incorporates the influence of the surrounding glia (dressed neurons). We predict seizurelike spontaneous oscillations in the absence of stimuli for strong coupling between neurons and astrocytes. Consistent with our predictions, a signature of this enhanced crosstalk, over expression of glutamate receptors in astrocytes, has been observed specifically in epileptic tissue.