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Signals that make waves

Neurons in the brain release proteins called neurotrophins, which bind to glial cells and unleash a wave of calcium ions inside them. This could be the missing link in a communication circuit between glia and neurons.

Our brains contain billions of nerve cells, woven together in an intricate network. But another class of brain cells, glial cells, vastly outnumbers the neurons. These cells provide essential support, forming a scaffold to hold the neurons in place, insulating the neuronal protrusions, providing nutrients and clearing debris. On page 74 of this issue, Rose et al.1 reveal another link between glial cells and neurons. Neurotrophins — proteins that bind to and promote the survival of neurons — also bind to astroglial cells. Rose et al. find that this binding triggers the release of calcium ions inside these cells. This might regulate communication between neurons.

Neurotrophins are crucial for the normal development and functioning of the brain. These proteins bind directly to neurons, triggering intracellular signals that culminate in survival, growth or the modulation of neuronal function. About a decade ago, the major receptors to which neurotrophins bind on neurons were shown to be a subfamily of 'receptor tyrosine kinases', named Trks (ref. 2). These receptors span the neuronal membrane; neurotrophin binding at the outside of the cell causes them to dimerize, which in turn activates the intracellular tyrosine-kinase portion of the receptor. This portion then phosphorylates other intracellular proteins, initiating signalling cascades inside the neurons. These lead to changes in protein function and gene expression that promote neuronal survival and maturation. The Trk receptors can also directly regulate other proteins in the neuronal membrane, including ion channels and receptors for neurotransmitters, which are essential for neuronal function3,4 (Fig. 1a).

Figure 1: A multifunctional receptor.

The TrkB receptor has various ways of regulating the ion concentrations in different brain cells. a, The full-length receptor occurs abundantly on the surface of neurons. When it binds its ligand, BDNF, the receptor's intracellular 'kinase' domain phosphorylates the enzyme phospholipase C, activating the transient receptor channel TRP. TrkB can also activate a sodium channel (Na(v)1.9) via a faster but less well understood interaction that probably does not require kinase activity. b, Astroglia contain a truncated form of the TrkB receptor (TrkB-T1). Its function was unclear, but Rose et al.1 now show that BDNF binding to this receptor activates the release of calcium from intracellular stores, through a signalling pathway that involves an as yet unidentified 'G protein'. This in turn promotes the generation of inositol trisphosphate (IP3) through phospholipase C. When IP3 binds to its intracellular receptor, calcium is released.

There are three trk genes, and each encodes more than one protein product. For instance, the trkB and trkC genes encode not only full-length TrkB and TrkC proteins, but also truncated forms lacking the intracellular tyrosine-kinase domain. However, little was known about the function of the truncated forms, as most studies of Trk receptors had involved the full-length, kinase-containing forms, which are abundant in neurons. The truncated forms are found mainly in glial cells, which lack the kinase-containing receptors. And the truncated form of TrkB is widely expressed both during development and in the adult brain.

What is the function of these truncated receptors, and why are they present on glial cells? Some clues, but no clear answers, have come from several studies. As the brain matures, the ratio of truncated to kinase-containing forms of TrkB increases dramatically in the outer layer of the brain (the cerebral cortex), indicating that the functions of the truncated receptors are developmentally regulated5. Truncated TrkB and TrkC have also been shown to form dimers with, and thereby inhibit the activation of, the full-length forms of these receptors. And truncated TrkB can rapidly bind and internalize the neurotrophins BDNF and NT4, preventing their diffusion6. Studies of cultured astroglia (matrix-forming glial cells in the brain) and Schwann cells (glial cells that insulate nerve-cell projections in the peripheral nervous system) have also revealed that truncated TrkB promotes both the internalization and subsequent release of BDNF. This suggests that these cells could act as a reservoir of BDNF to promote the growth and maturation of adjacent neurons7. Finally, several groups have shown that the truncated receptors can, through more direct mechanisms, regulate the neurons' intracellular pH and maturation, but what these mechanisms might be has been somewhat enigmatic8,9,10.

Rose et al.1 now take a step towards solving this enigma. They show that when BDNF is applied to cultures of astroglia and slices of brain, it generates waves of calcium release inside the glial cells. Calcium is an important 'second messenger' that regulates the release of neurotransmitters and other molecules from cells, as well as controlling the activities of several signalling proteins and ion channels. BDNF is released by neurons and is present in the brain at the sub-nanomolar concentrations required to generate calcium waves, so this protein might be a means by which neurons signal to glia.

The authors show that the BDNF-induced production of calcium waves in astroglia requires truncated ('T1'), but not kinase-containing, TrkB. And wave generation requires intracellular but not extracellular calcium — waves are prevented by inhibiting a receptor, the inositol trisphosphate receptor, through which calcium is released from intracellular compartments. Rose and colleagues' study also implicates several other signalling molecules in the pathway from receptor activation to wave generation (Fig. 1b). These include an as yet unidentified G protein (a class of protein that often couples cellular receptors to intracellular signalling pathways) and phospholipase C (an enzyme that generates inositol trisphosphate from phospholipids). It will be important to identify the G protein involved in this signalling cascade.

What is the significance of the waves of calcium release in astroglia? In so-called pyramidal neurons of the cerebral cortex, both the expression and release of BDNF are induced by calcium and electrical activity. And in adjacent astroglia, increased levels of calcium evoke the release of the excitatory neurotransmitter glutamate, enhancing the activity of the synapses formed by neighbouring neurons11. (Synapses are the connections through which electrical impulses can pass from one neuron to the next.) Calcium waves can also propagate through many astroglia and regulate synapses over wide areas by means of gap junctions, which are connections between cells that allow molecules to move from one cell to another11.

It was known that BDNF promotes both short- and long-term enhancement of synaptic strength, but the underlying mechanisms were poorly understood. Rose and colleagues' findings1 suggest that it may exert its effects on neuronal synapses in part by triggering calcium signalling in astroglia. The physiological functions of this signalling pathway, and which of the other truncated forms of TrkB and TrkC can initiate it, remain to be discovered.


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