Many critical discoveries have underlined the importance of astrocytes in establishing a synaptic connection in the developing brain. In this article, we review the key findings of astrocytes function and elimination of synapses. First, we summarize our current structural and functional understanding of astrocytes in the synapse. Next, we will discuss the cellular and molecular mechanisms by which developing and mature astrocytes instruct the formation, maturation, and refinement of synapses. Our goal is to provide a review of astrocytes as important players in creating a functional nervous system.
In the central nervous system (CNS), astrocytes are closely related to synapses. Through this linkage, astrocytes can monitor and change synaptic functions, actively controlling synaptic transmission. This close structural and functional partnership of the perisynaptic astrocyte process with pre- and postsynaptic neuronal structures led to the concept of a “triple synapse” (Araque et al. 1999). In addition to their important role in adult synapses, in the last three decades, many critical discoveries have underlined the importance of astrocytes in establishing a synaptic connection in the CNS. These findings fundamentally changed the way we perceive astrocytes and lead to the birth of a thriving area of cell neuroscience.
Our goal is to provide a current understanding of astrocytes as active participants in the construction of synaptic circuits. In this article, we review key findings of astrocytic control of the formation, function, and elimination of synapses. We will start by evaluating our structural and astrocytes function understanding of astrocytes in the synapse. Next, we will discuss in detail the molecular mechanisms by which developing and mature astrocytes instruct the formation, maturation, and refinement of synapses. Along the way, we will also highlight important gaps in our knowledge that should be addressed in future research.
Astrocytes interact closely with the surrounding structures in the nervous system and contribute to the regulation of their function. For example, astrocyte processes contribute to the reduction of glial nerve conduits, and astrocyte contact limbs contact blood vessels and control blood flow. Astrocytes also closely bind to neuronal myomas, axons, dendrites, and synapses.
However, the functional meaning of this phenomenon and the molecular mechanisms controlling this process are largely unknown. Placement of astrocyte plates may be crucial for the proper functioning of the nervous system because in disease states and after injuries, the astrocytes lose their plaques and display a mixed morphology of the process (Oberheim et al. 2009).
(Astrocytes function) Segregate Processes Adjacent Synapses
One of the most important functions of astrocytes in the synapse is the removal of neurotransmitters. For example, astrocyte processes associated with excitatory synapses are coated with glutamate transporters that maintain a low level of surrounding glutamate in the CNS and shape the activation of glutamate receptors in synapses. astrocytes function processes may have a specific attraction in relation to postsynaptic sites.
It turned out that the occurrence of astrocyte processes was three to four times higher compared to presynaptic (Lehre and Rusakov 2002). Due to the asymmetric location of astrocytes in excitatory synapses, glutamate escaping into the synaptic cleft is 2-4 times more susceptible to the activation of glutamate receptors, which are located on the periphery of the presynaptic side as compared to the non-synaptic receptors in the spines.
This asymmetry is even more exaggerated in the cerebellum, in which Bergman glues the majority of Purkinje cell spines (Grosche et al. 1999). These observations suggest that the interaction of astrocytes with the synapse promotes rapid presynaptic feedback due to overgrowth of glutamate while preserving the specificity of postsynaptic transmission (Rusakov and Lehre 2002).
The interactions of astrocytes with synapses are dynamic
Time-lapse imaging of astrocytes and dendrites in organotypic sections from different brain regions demonstrates the dynamic nature of small astrocytic processes because they rapidly elongate and insert to engage and detach from postsynaptic dendritic spines. In the brainstem, astrocyte processes interact with neuronal dendrites and spines through at least two distinct microstructures: flat astrocytes similar to lamellipodia and more transient astrocytes similar to filopodia (Grass et al. 2004). Similarly, astrocyte processes actively interact with neuronal dendrites and spines in the mouse hippocampus (Murai et al. 2003, Haber et al. 2006).
interaction of astrocytes
Current molecular knowledge about the interaction of astrocytes with synapses is limited; however, a mechanism mediated by contact involving bi-directional ephrin / EphA signaling has been previously described (Murai et al. 2003). In the hippocampus, astrocytes function and their processes express ephrin A3, whereas neurons express the effa4 receptor.
Transmission of ephrin / EphA signal by supplying soluble ephrin A3 in hippocampal patch cultures or by transfection of neurons with inactive EphA4 kinase causes defects in spine formation and maturation. Similarly, mice lacking ephA4 or ephrin-3A have abnormal spinal morphology (Carmona et al. 2009, Filosa et al. 2009). It is possible that activity-dependent mechanisms regulating ephrin / EphA signaling can modulate the synapse effects of synapses, thus controlling synaptic stability and potentially also eliminating and refining the synapse.
In summary, astrocyte processes closely affect neuronal synapses throughout life, and this interaction is highly dynamic, allowing continuous modulation of synaptic functions by astrocytes.