Synaptic environment and extrasynaptic glutamate signals: The quest continues

Behaviour of a mammal relies on the brain's excitatory circuits equipped with glutamatergic synapses. In most cases, glutamate escaping from the synaptic cleft is rapidly buffered and taken up by high-affinity transporters expressed by nearby perisynaptic astroglial processes (PAPs). The spatial relationship between glutamatergic synapses and PAPs thus plays a crucial role in understanding glutamate signalling actions, yet its intricate features can only be fully appreciated using methods that operate beyond the diffraction limit of light. Here, we examine principal aspects pertaining to the receptor actions of glutamate, inside and outside the synaptic cleft in the brain, where the organisation of synaptic micro-physiology and micro-environment play a critical part. In what conditions and how far glutamate can escape the synaptic cleft activating its target receptors outside the immediate synapse has long been the subject of debate. Evidence is also emerging that neuronal activity- and astroglia-dependent glutamate spillover actions could be important across the spectrum of cognitive functions This article is part of the special issue on 'Glutamate Receptors - The Glutamatergic Synapse'.