34 research outputs found
A computational study of astrocytic glutamate influence on post-synaptic neuronal excitability
<p><b>Postsynaptic activity due to synaptic and intrinsic currents</b>, triggered by (a) synaptic glutamate [Glu]<sub>syn</sub> (b-d) simulation with [Glu]<sub>ast,eq</sub> = 1.5mM, 5mM, and 10mM respectively, synaptic currents (I<sub>syn</sub>) combined AMPA- and NMDA-mediated currents in response to synaptic glutamate, membrane potential (V<sub>m</sub>) of postsynaptic neuron resulting from combination of I<sub>syn</sub> and voltage-gated currents (Na<sup>+</sup>, K<sup>+</sup> and leak). Prolonged time course of synaptic glutamate leads to enhanced synaptic currents (I<sub>syn</sub>) and higher frequency postsynaptic firing response (V<sub>m</sub> depolarisations) as [Glu]<sub>ast,eq</sub> increases.</p
A Computational Study of Astrocytic GABA Release at the Glutamatergic Synapse: EAAT-2 and GAT-3 Coupled Dynamics
Neurotransmitter dynamics within neuronal synapses can be controlled by astrocytes and reflect key contributors to neuronal activity. In particular, Glutamate (Glu) released by activated neurons is predominantly removed from the synaptic space by perisynaptic astrocytic transporters EAAT-2 (GLT-1). In previous work, we showed that the time course of Glu transport is affected by ionic concentration gradients either side of the astrocytic membrane and has the propensity for influencing postsynaptic neuronal excitability. Experimental findings co-localize GABA transporters GAT-3 with EAAT-2 on the perisynaptic astrocytic membrane. While these transporters are unlikely to facilitate the uptake of synaptic GABA, this paper presents simulation results which demonstrate the coupling of EAAT-2 and GAT-3, giving rise to the ionic-dependent reversed transport of GAT-3. The resulting efflux of GABA from the astrocyte to the synaptic space reflects an important astrocytic mechanism for modulation of hyperexcitability. Key results also illustrate an astrocytic-mediated modulation of synaptic neuronal excitation by released GABA at the glutamatergic synapse
Potassium and sodium microdomains in thin astroglial processes: A computational model study
A biophysical model that captures molecular homeostatic control of ions at the perisynaptic cradle (PsC) is of fundamental importance for understanding the interplay between astroglial and neuronal compartments. In this paper, we develop a multi-compartmental mathematical model which proposes a novel mechanism whereby the flow of cations in thin processes is restricted due to negatively charged membrane lipids which result in the formation of deep potential wells near the dipole heads. These wells restrict the flow of cations to “hopping” between adjacent wells as they transverse the process, and this surface retention of cations will be shown to give rise to the formation of potassium (K+) and sodium (Na+) microdomains at the PsC. We further propose that a K+ microdomain formed at the PsC, provides the driving force for the return of K+ to the extracellular space for uptake by the neurone, thereby preventing K+ undershoot. A slow decay of Na+ was also observed in our simulation after a period of glutamate stimulation which is in strong agreement with experimental observations. The pathological implications of microdomain formation during neuronal excitation are also discussed
Identifying Key Predictors of Cognitive Dysfunction in Older People Using Supervised Machine Learning Techniques: Observational Study
Background: Machine learning techniques, specifically classification algorithms, may be effective to help understand key health, nutritional, and environmental factors associated with cognitive function in aging populations.
Objective: This study aims to use classification techniques to identify the key patient predictors that are considered most important in the classification of poorer cognitive performance, which is an early risk factor for dementia.
Methods: Data were used from the Trinity-Ulster and Department of Agriculture study, which included detailed information on sociodemographic, clinical, biochemical, nutritional, and lifestyle factors in 5186 older adults recruited from the Republic of Ireland and Northern Ireland, a proportion of whom (987/5186, 19.03%) were followed up 5-7 years later for reassessment. Cognitive function at both time points was assessed using a battery of tests, including the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), with a score
Results: In the classification of a low RBANS score (
Conclusions: The results suggest that it may be possible for a health care professional to make an initial evaluation, with a high level of confidence, of the potential for cognitive dysfunction using only a few short, noninvasive questions, thus providing a quick, efficient, and noninvasive way to help them decide whether or not a patient requires a full cognitive evaluation. This approach has the potential benefits of making time and cost savings for health service providers and avoiding stress created through unnecessary cognitive assessments in low-risk patients
Recommended from our members
The influence of astrocytic leaflet motility on ionic signalling and homeostasis at active synapses
Astrocytes display a highly complex, spongiform morphology, with their fine terminal processes (leaflets) exercising dynamic degrees of synaptic coverage, from touching and surrounding the synapse to being retracted from the synaptic region. In this paper, a computational model is used to reveal the effect of the astrocyte-synapse spatial relationship on ionic homeostasis. Specifically, our model predicts that varying degrees of astrocyte leaflet coverage influences concentrations of K+, Na+ and Ca2+, and results show that leaflet motility strongly influences Ca2+ uptake, as well as glutamate and K+ to a lesser extent. Furthermore, this paper highlights that an astrocytic leaflet that is in proximity to the synaptic cleft loses the ability to form a Ca2+ microdomain, whereas when the leaflet is remote from the synaptic cleft, a Ca2+ microdomain can form. This may have implications for Ca2+-dependent leaflet motility
Schematic representations of the two pathways in the model.
<p>(a) Direct pre- to post-synaptic neuron transmission only, passive astrocyte responsible for glutamate uptake (dotted line). (b) Indirect pre-to post-synaptic (via astrocyte activation) transmission only.</p
A computational study of astrocytic glutamate influence on post-synaptic neuronal excitability - Fig 6
<p><b>Stability diagram of astrocytic calcium activity in the (a) soma and (b) perisynaptic process, [Ca</b><sup><b>2+</b></sup><b>]</b><sub><b>ast</b></sub>, <b>on frequency of periodic presynaptic firing activity under different baseline astrocytic level [Glu]</b><sub><b>ast,eq</b></sub>. (o) denotes upper and lower amplitudes of oscillation at steady state. Lower bound of induced oscillatory regime is increased with decreasing [Glu]<sub>ast,eq</sub>. Demonstrates a clear range of input presynaptic firing frequencies which result in Ca<sup>2+</sup> activation across the three measured [Glu]<sub>ast,eq</sub>. where increasing [Glu]<sub>ast,eq</sub> correlates with reduction in the lower limit of this range.</p
Compartmental model of tripartite glutamatergic synapse.
<p>(1) A 10 Hz simulated spike train mimicking <i>in vivo</i> spontaneous activity results in a deterministic release of vesicular glutamate and voltage-dependent potassium (K<sup>+</sup>) efflux from the presynaptic neuron into the synaptic cleft: (2a) Glutamate (Glu<sup>-</sup>) activates N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on the postsynaptic neuron and (2b) Metabotropic glutamate receptors (mGluRs) located on the astrocytic membrane: (3) Glu<sup>-</sup> is removed from the synaptic cleft compartment by sodium (Na<sup>+</sup>) dependent excitatory amino-acid transporters (EAATs): (4) Glu<sup>-</sup> and 3Na<sup>+</sup> enters the astrocytic compartment, the former to be either converted to glutamine or α-ketoglutarate, or packaged into vesicles: (5) Activation of the astrocytic mGluRs results in production of inositol 1, 4, 5-trisphosphate (IP<sub>3</sub>): (6) IP<sub>3</sub> opens Ca<sup>2+</sup> channels on the endoplasmic reticulum (ER) allowing an efflux of Ca<sup>2+</sup> into the cytoplasm in both the soma and perisynaptic process compartments: (7) Ca<sup>2+</sup> elevation in the process stimulates the release of glutamate vesicles: (8) Astrocytic released glutamate binds to extrasynaptic glutamate receptors: (9) A slow inward current (SIC) is generated in the post-synaptic compartment: Astrocytic homeostatic (10a) Sodium/Potassium pump (NaK-ATPase) removes Na<sup>+</sup><sub>ast.</sub> and K<sup>+</sup><sub>syn</sub> (10b) Sodium-Calcium exchanger (NCX) exchanges 1Ca<sup>2+</sup> for 3Na<sup>+</sup> across the membrane.</p