Abstract
The discovery of participation of astrocytes as active elements in glutamatergic tripartite synapses (composed by functional units of two neurons and one astrocyte) has led to the construction of models of cognitive functioning in the human brain, focusing on associative learning, sensory integration, conscious processing and memory formation/retrieval. We have modelled human cognitive functions by means of an ensemble of functional units (tripartite synapses) connected by gap junctions that link distributed astrocytes, allowing the formation of intra- and intercellular calcium waves that putatively mediate large-scale cognitive information processing. The model contains a diagram of molecular mechanisms present in tripartite synapses and contributes to explain the physiological bases of cognitive functions. It can be potentially expanded to explain emotional functions and psychiatric phenomena.
Highlights
Recent research focusing on the participation of astrocytes in glutamatergic synapses has revealed a connection between the following four human cognitive functions: learning, perception, conscious processing and memory formation/ retrieval
The discovery of the participation of astrocytes as active elements in synaptic transmission/computation has led to the construction of broader models, composed by functional units of two neurons and one astrocyte, the tripartite synapses [Figure 1]
We strongly suggest that the astroglial network, together with other glial cells, blood and cerebrospinal fluid, constitutes a brain-wide signalling circuit supplementary to neuronal networks
Summary
Astrocytes compose one-half of brain tissue volume, until recently only passive functions were attributed to these star-shaped cells, such as giving. Hippocampal neuron activates AMPA receptors and the resulting depolarization opens NMDA receptors of the NR2A subtype, promoting calcium ion entry that cause membrane potentiation related to associative learning (mostly by means of a signalling cascade and gene expression that leads to an increase in AMPA-dependent response); b) At the same time, the glutamatergic input activates metabotropic receptors in the membrane of one single astrocyte that wraps almost all such active synapses; c) When such local glutamatergic converging input are synchronised, the resulting (additive) stimulation over the membrane of the astrocyte crosses a given threshold and elicits coherent, amplitude- and/or frequencymodulated calcium waves with the potential of integrating local information [Figure 3]; d) When global brain synchronisation occurs, calcium waves integrate sensory, cognitive and affective/emotional patterns from distinct neuronal populations; e) Glutamate released from astrocytes to postsynaptic neurons in tripartite synapses binds to extrasynaptic NMDA receptors of the NR2B subtype, which drives slow inward calcium currents, causing a delayed depolarization and an increase of CaMKII phosphorylation and AMPA excitability, a process we called “meta-potentiation” (Pereira Jr and Furlan, 2007) and reinforces journal long-term potentiation, or alternatively triggers a process of long-term depression. The consideration of astrocytecognitive and affective functions affords a reconceptualizationof whole brain function and generation of automatic and voluntary behaviors, as well as psychosomatic effects
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