Brain functions such as learning, memory and consciousness are based on the information processing at cellular and molecular levels. Until very recently synaptic physiology dominated in neuroscience. Brain viewed as a large network of neurons connected to each other via synapses, mainly chemical and less often electrical. Neurons served as non-linear integrators of synaptic inputs and coincidence detectors. The information thought to be stored solely in a form of synaptic plasticity. Therefore, scientific research was focused on presynaptic mechanisms of neurotransmitter release and properties of postsynaptic neurotransmitter receptors. However, due to technological advance of neuroscience techniques “the inconvenient truth” has emerged. Functional receptors were found outside of the synapses, various synaptic and extrasynaptic sources of their ligands were identified.
Extrasynaptic Receptors
During recent years, many publications addressed properties and functions of extrasynaptic receptors. The interest of scientific community in this field can be seen from the annual increase in number of reports presented at Society for Neuroscience (USA) meeting, the largest neuroscience meeting in the World. Previously we have discovered that GABAA receptors can regulate propagation of information in hippocampal neuronal network in cell type specific manner. We also found that activation of axonal kainate receptors in axons of hippocampal interneurons can trigger ectopic action potentials. Now using two photon microscopy and simultaneous glutamate uncaging, we are studying functions of extrasynaptic NMDA receptors in hippocampal pyramidal cells. The presence of extrasynaptic receptors opens an intriguing possibility that brain cells can communicate to each other by chemical signals even if they do not have synaptic connections among them. Interestingly these extrasynaptic receptors can be activated by the same agonists as synaptic receptors (e.g. GABA and glutamate). The difference is usually in the biophysical properties: extrasynaptic receptors tend to have higher affinity and slower desensitization kinetics. Thus clinically used drugs can also (and maybe preferentially) target extrasynaptic receptors. This can explain their side effects that are sometimes “mysterious” to synaptic physiologists.
Spillover of Neurotransmitters
Presence of functional extrasynaptic receptors is necessary but not sufficient condition for cell-to-cell non-synaptic communication. The receptors require sources of the agonists. Several lines of research pointed that extrasynaptic signals are actually very complex. More than a decade ago Dimitri Kullmann suggested that glutamate can escape the synaptic cleft and reach glutamate receptors on the neighbouring synapses. This phenomenon was named “spillover” and initially proposed to be a mechanism of intersynaptic crosstalk. These days, spillover of neurotransmitters is considered to play a role in activation of high affinity extrasynaptic receptors. Glutamate spillover can activate extrasynaptic NMDA receptors, kainate receptors, and metabotropic glutamate receptors. GABA escaping from the synaptic cleft acts on extrasynaptic GABAB receptors and is responsible for tonic activation of extrasynaptic GABAA receptors.
Release by Astrocytes
Another important observation was that not only neurons, but also astrocytes can release glutamate and GABA. Astrocytes are the most numerous cells in the brain. They outnumber neurons approximately ten times and coupled via gap-junctions. The mechanisms by which signaling molecules are released from astrocytes are largely unknown.
Calcium dependent vesicular release of glutamate has been suggested. The mechanisms that regulate slow spontaneous calcium oscillations in astrocytes are poorly understood. It is also unclear how the calcium signals can propagate within the astrocytic networks. To address this question we employ confocal laser scanning microscopy and record calcium signal from the astrocytes loaded with fluorescent dyes. The astrocytes also possess various neurotransmitter receptors, and thus can participate in bi-directional diffuse communication with neurons.
Hypothesis of “Guiding Template”
Certainly our work does not undermine the importance of synaptic transmission and plasticity in the brain. Extrasynaptic signaling can affect the synaptic networks by acting on synapses or by changing neuronal excitability. Distributed sources of signaling molecules (synaptic spillover, non-synaptic neuronal release, astrocytes) spatially co-exist with synaptic networks and form a concentration profile of ambient agonists to extrasynaptic receptors. This profile is shaped by anisotropy of diffusion and uptake. Inhomogeneous extrasynaptic signals form a template that guides the information propagation in the synaptic networks. Such a “guiding template” could be potentially as important as synaptic plasticity for information processing in the brain.
Thus, to make significant progress and step from cellular to systemic level we have to look carefully for the types of communication between brain cells, consider the link between neurons and astrocytes, and information processing in synapse and beyond. In addition to fundamental understanding of brain functions this approach can be useful for developing better and more specific medicines; for simulations of the neuronal networks and building artificial intelligence; more accurate system for automation and control.
