Department of Medical Physiology and Biophysics. Avenida Sánchez Pizjuán 4. University of Seville. Seville. 41900. Spain.

Since the emergence of the tripartite synapse concept, mounting evidence has revealed that astrocytes can control information flow in a circuit-specific way, particularly for a form of synaptic plasticity, namely Spike Timing-Dependent Plasticity (STDP). Based on our recent findings we could say that astrocytes frame the activity coincidence for STDP as a temporal detection traffic light (e.g., favouring the induction of Long-Term Depression (t-LTD) by D-serine release at postnatal (P) days 13-21 (P13-P21) ¹, closing a plasticity window due to adenosine release at P22-P30 ² or further gating a new plasticity window for Long-Term Potentiation due to glutamate release at P34-P42 in mice hippocampal CA1 synapses ³. These findings and the recent similarities found in the mouse primary somatosensory cortex (S1) allow us to hypothesize that in the mouse hippocampus and S1, astrocytes aid or prevent firing coincidence by providing selective gliotransmitters during coincident spiking, depending on the developmental stage. In line with this, it is known that neurotransmitter-evoked activation of astrocytes leads to astrocytic release of glutamate, D-serine, ATP, and/or adenosine, which through the activation of the corresponding pre- and postsynaptic receptors establishes a threshold for basal synaptic transmission, and enhances short- and long-term synaptic plasticity. Astrocytes gradually increase their Ca²⁺ signalling during the induction of t-LTD in a cannabinoid receptor 1 (CB₁R)-dependent manner at synapses between excitatory neurons in somatosensory cortical layer 4 and layer 2/3 (L4-L2/3 synapses). Interestingly, at L4-L2/3 synapses of the primary somatosensory cortex, stimulation of the astrocyte coincident with afferent activity results in LTD. This has also been observed during coincident stimulation of Schaffer collaterals and astrocytes in area CA1 of the hippocampus, and we have observed it recently in horizontal L2/3-L2/3 synapses of S1 involving astrocytic release of D-serine as a prerequisite ⁴. Preliminarily, we have observed that a form of synaptic plasticity involving brain rhythms interactions involves astrocyte signalling, and astrocytes dictate the magnitude of this plasticity and sense the timing coincidence of rhythms interaction. This type of plasticity, named theta-nested gamma oscillations-induced Long-Term Potentiation (TnG-LTP), is impaired at 2 months of age in an Alzheimer’s disease model (App-tau mice), far before amyloid and tau pathology and clinical onset of cognitive impairment. This is controversial, since plasticity induced with conventional protocols appears disrupted only at later stages of the disease, probably because these protocols do not consider the oscillatory activity of the network and the interaction of theta and gamma rhythms. Thus, TnG-LTP might have an impact on functions that are acquired later during development. Additionally, astrocytes may play a role in setting a threshold for the induction of plasticity during development, and this could represent a promising mechanism to target in Alzheimer´s disease models.