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Astrocytes have for decades been considered as non-excitable support cells of the central nervous system (CNS). However, this view has changed radically during the last thirty years. Astrocytes have come to the forefront of neuroscience in our attempt to gain a better understanding of the cellular mechanisms underlying synaptic transmission. Astrocytes express a variety of surface receptors for common neurotransmitters, e.g., glutamate and acetylcholine. Additionally, astrocytes respond to stimulation by releasing gliotransmitters such as glutamate. These properties have led to the concept of tripartite synapse involving bidirectional communication between neurons and astrocytes. This review aims at summarizing current evidence for how astrocytes are involved in modulating synaptic transmission within cortical regions of the CNS. The activation of metabotropic- and ionotropic receptors expressed in astrocytes triggers an increase in their intracellular Ca2+ concentration, which in turn promotes the release of glutamate. The astrocyte released glutamate stimulate either group I or II and III metabotropic glutamate receptors (mGluRs) on presynaptic terminals. Depending on the type of activated presynaptic mGluR, astrocytic glutamate may either potentiate or depress synaptic transmission. In summary, astrocytes are actively participating in the modulation of synaptic transmission within cortical regions of the CNS. Astrocytes may consequently be a potential therapeutic target for brain pathological illnesses, e.g., neurodegeneration during ischemic stroke.