Search Results (4)

Once outside the synaptic cleft, the excitatory neurotransmitter glutamate is rapidly bound by its high-affinity transporters, which are expressed in abundance on the surface of perisynaptic astroglia. While this binding and the subsequent uptake of glutamate constrain excitatory transmission mainly within individual synapses, there is growing evidence for the physiologically important extrasynaptic actions of glutamate. However, the mechanistic explanation and the scope of such actions remain obscure. Furthermore, a significant proportion of glutamate molecules initially bound by transporters could be released back into the extracellular space before being translocated into astrocytes. To understand the implications of such effects, we simulated the release, diffusion, and transporter and receptor interactions of glutamate molecules in the synaptic environment. The latter was represented via trial-by-trial stochastic generation of astroglial and neuronal elements in the brain neuropil (overlapping spheroids of varied sizes), rather than using the ‘average’ morphology, thus reflecting the probabilistic nature of neuropil architectonics. Our simulations predict significant activation of high-affinity receptors, such as receptors of the NMDA type, at distances beyond half-micron from the glutamate release site, with glutamate–transporter unbinding playing an important role. These theoretical predictions are consistent with recent glutamate imaging data, thus lending support to the concept of significant volume-transmitted actions of glutamate in the brain. Full article

The mathematical modeling of synaptically connected neuronal networks is an established instrument for gaining insights into dynamics of neuronal ensembles and information processing in the nervous system. Recently, calcium signaling in astrocytes—glial cells controlling local tissue metabolism and synapse homeostasis—and its corresponding downstream effect on synaptic plasticity and neuromodulation appeared in the limelight of modeling studies. Here, we used mechanism-based mathematical modeling to disentangle signaling pathways and feedback loops in the astrocytic calcium response to noradrenaline, an important neuromodulator marking periods of heightened alertness and arousal. The proposed model is based on an experiment-based 2D representation of astrocyte morphology, discrete random glutamate synapses with placement probability defined by the morphology pattern, and spatially heterogeneous noradrenaline sources, reflecting axonal varicosities of the adrenergic axons. Both glutamate and noradrenaline drive Ca${}^{2+}$ dynamics in the astrocyte in an additive or synergistic manner. Our simulations replicate the global activation of astrocytes by noradrenaline and predict the generation of high-frequency Ca${}^{2+}$ waves in a dose-dependent manner and the preferred Ca${}^{2+}$ wave origination near noradrenaline release sites if they colocalise with high-density clusters of glutamate synapses. We tested positive feedback loops between noradrenaline release and glutamate spillover directly or mediated by gliotransmitter release from the activated astrocyte. The simulations suggest that the coupled stochastic drive by glutamate and noradrenaline release converges on the graded modulation of the IP${}_3$ level, which is translated into whole-cell Ca${}^{2+}$ waves of different frequencies. Thus, the proposed approach is supported by experimental data and can be used to address situations inaccessible directly by experiment, and is a starting point for a more detailed model that includes other signaling mechanisms providing negative feedback. Full article

Excitatory synapses in the brain are often surrounded by nanoscopic astroglial processes that express high-affinity glutamate transporters at a high surface density. This ensures that the bulk of glutamate leaving the synaptic cleft is taken up for its subsequent metabolic conversion and replenishment in neurons. Furthermore, variations in the astroglial coverage of synapses can thus determine to what extent glutamate released into the synaptic cleft could activate its receptors outside the cleft. The biophysical determinants of extrasynaptic glutamate actions are complex because they involve a competition between transporters and target receptors of glutamate in the tortuous space of synaptic environment. To understand key spatiotemporal relationships between the extrasynaptic landscapes of bound and free glutamate, we explored a detailed Monte Carlo model for its release, diffusion, and uptake. We implemented a novel representation of brain neuropil in silico as a space filled with randomly scattered, overlapping spheres (spheroids) of distributed size. The parameters of perisynaptic space, astroglial presence, and glutamate transport were constrained by the empirical data obtained for the ‘average’ environment of common cortical synapses. Our simulations provide a glimpse of the perisynaptic concentration landscapes of free and transporter-bound glutamate relationship, suggesting a significant tail of space-average free glutamate within 3 ms post-release. Full article

Disrupted glutamate clearance in the synaptic cleft leads to synaptic dysfunction and neurological diseases. Decreased glutamate removal from the synaptic cleft is known to cause excitotoxicity. Data on the physiological effects of increased glutamate clearance are contradictory. This study investigated the consequences of ceftriaxone (CTX), an enhancer of glutamate transporter 1 expression, treatment on long-term synaptic potentiation (LTP) in the hippocampus of young rats. In this study, 5-day administration of CTX (200 mg/kg) significantly weakened LTP in CA3-CA1 synapses. As shown by electrophysiological recordings, LTP attenuation was associated with weakening of N-Methyl-D-aspartate receptor (NMDAR)-dependent signaling in synapses. However, PCR analysis did not show downregulation of NMDAR subunits or changes in the expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits. We assume that extracellular burst stimulation activates fewer synapses in CTX-treated animals because increased glutamate reuptake results in reduced spillover, and neighboring synapses do not participate in neurotransmission. Attenuation of LTP was not accompanied by noticeable behavioral changes in the CTX group, with no behavioral abnormalities observed in the open field test or Morris water maze test. Thus, our experiments show that increased glutamate clearance can impair long-term synaptic plasticity and that this phenomenon can be considered a potential side effect of CTX treatment. Full article