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.

The ability of astrocytes to rapidly clear synaptic glutamate and purposefully release the excitatory transmitter is critical in the functioning of synapses and neuronal circuits. Dysfunctions of these homeostatic functions have been implicated in the pathology of brain disorders such as mesial temporal lobe epilepsy. However, the reasons for these dysfunctions are not clear from experimental data and computational models have been developed to provide further understanding of the implications of glutamate clearance from the extracellular space, as a result of EAAT2 downregulation: although they only partially account for the glutamate clearance process. In this work, we develop an explicit model of the astrocytic glutamate transporters, providing a more complete description of the glutamate chemical potential across the astrocytic membrane and its contribution to glutamate transporter driving force based on thermodynamic principles and experimental data. Analysis of our model demonstrates that increased astrocytic glutamate content due to glutamine synthetase downregulation also results in increased postsynaptic quantal size due to gliotransmission. Moreover, the proposed model demonstrates that increased astrocytic glutamate could prolong the time course of glutamate in the synaptic cleft and enhances astrocyte-induced slow inward currents, causing a disruption to the clarity of synaptic signalling and the occurrence of intervals of higher frequency postsynaptic firing. Overall, our work distilled the necessity of a low astrocytic glutamate concentration for reliable synaptic transmission of information and the possible implications of enhanced glutamate levels as in epilepsy.

It has recently been proposed using a multi-compartmental mathematical model that negatively fixed charged membrane-associated sites constrain the flow of cations in perisynaptic astroglial processes. This restricted movement of ions between the perisynaptic cradle (PsC), principal astroglial processes and the astrocyte soma gives rise to potassium (K + ) and sodium (Na + ) microdomains at the PsC. The present paper extends the above model to demonstrate that the formation of an Na + microdomain can reverse the Na + /Ca 2+ exchanger (NCX) thus providing an additional source of calcium (Ca 2+ ) at the PsC. Results presented clearly show that reversal of the Na + /Ca 2+ exchanger is instigated by a glutamate transporter coupled increase in concentration of cytoplasmic [Na + ] i at the PsC, which and instigates Ca 2+ influx through the NCX. As the flow of Ca 2+ along the astrocyte process and away from the PsC is also constrained by Ca 2+ binding proteins, then a Ca 2+ microdomain forms at the PsC. The paper also serves to demonstrate that the EAAT, NKA, and NCX represent the minimal requirement necessary and sufficient for the development of a Ca 2+ microdomain and that these mechanisms directly link neuronal activity and glutamate release to the formation of localized Na + and Ca 2+ microdomains signals at the PsC. This local source of Ca 2+ can provide a previously underexplored form of astroglial Ca 2+ signaling.

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 <70 classed as poorer cognitive performance. This study trained 3 classifiers—decision trees, Naïve Bayes, and random forests—to classify the RBANS score and to identify key health, nutritional, and environmental predictors of cognitive performance and cognitive decline over the follow-up period. It assessed their performance, taking note of the variables that were deemed important for the optimized classifiers for their computational diagnostics. Results In the classification of a low RBANS score (<70), our models performed well (F1 score range 0.73-0.93), all highlighting the individual’s score from the Timed Up and Go (TUG) test, the age at which the participant stopped education, and whether or not the participant’s family reported memory concerns to be of key importance. The classification models performed well in classifying a greater rate of decline in the RBANS score (F1 score range 0.66-0.85), also indicating the TUG score to be of key importance, followed by blood indicators: plasma homocysteine, vitamin B6 biomarker (plasma pyridoxal-5-phosphate), and glycated hemoglobin. 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.

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.