© INSERM/CNRS 2006 In normal conditions, NMDA receptors are activated by D-serine released from astrocytes. In lactating animals (right), glial cells retract, and there are not enough NMDA receptors activated to trigger long-term neuronal activity.
© INSERM/CNRS 2006
In normal conditions, NMDA receptors are activated by D-serine released from astrocytes. In lactating animals (right), glial cells retract, and there are not enough NMDA receptors activated to trigger long-term neuronal activity.
Glial cells, most often referred to as “neuroglia” or simply “glia,” play crucial roles in the central nervous system, where they outnumber neurons 10 to 1. During early development, they guide the migration of neurons and influence the growth of their axons and dendrites. In mature organisms, they provide physical support and transfer energy from the blood circulation to the nerves. Glial cells are also known to have a protective role by clearing leftover ions and neurotransmitters from the synaptic cleft, where their accumulation could become toxic to neighboring neurons. But in the last decade, scientists discovered that neuroglia played yet another major role.
Glial cells, in particular astrocytes–the star-shaped cells that make up the “cement” between neurons–seem to have their own say in synaptic transmission and neuronal excitability. A new concept is thus emerging, that of “tripartite synapses,” which involve glial cells in addition to the usual neuronal extremities.
“First, advances in technology, especially in calcium imaging, showed that glial cells–which were always considered unexcitable–could actually be stimulated,” explains CNRS researcher Stéphane Oliet.1 “We then discovered that, when stimulated, they liberate their own substances, called 'gliotransmitters,' which have a direct effect on neighboring neurons.”
Different gliotransmitters have since been identified, such as ATP, glutamate, and D-serine. While ATP and glutamate target ATP and glutamate receptors respectively, D-serine acts as a co-activator upon so-called NMDA glutamate receptors. NMDA receptors play a critical role in synaptic plasticity–the cellular mechanism at the basis of memory and learning processes. To become active, the receptor needs two agonists to bind it simultaneously. One of them, glutamate, is released by presynaptic nerves and by the glia. Although several candidates have been put forward as potential co-ligands, evidence is accumulating in favor of D-serine.
In a study recently published in Cell,2 Oliet and his team demonstrated for the first time that in the rat hypothalamus, the D-serine necessary for NMDA receptor activation originates solely from neighboring astrocytes, thus confirming the tripartite synapse model.
Working on hypothalamic brain slices from rats, the researchers first demonstrated that D-serine is the endogenous co-ligand of the NMDA receptor. Their electrophysiological experiments showed that when D-serine was removed from the synaptic cleft, NMDA receptors could not be activated. Furthermore, both bio- and immunochemistry experiments led to the conclusion that, in this region of the brain, D-serine and its synthesizing enzyme are only present in astrocytes. “So in fact, the receptor's co-ligand is a gliotransmitter and not a neurotransmitter, as one would have traditionally expected,” says Oliet.
The team was then eager to verify a naturally ensuing hypothesis. If glial cells are important for the activation of NMDA receptors in the hypothalamus, they must also influence processes that depend on these receptors, such as synaptic plasticity. To test this hypothesis, the team took advantage of a physiological particularity of the hypothalamus' anatomy.
In the hypothalamus during lactaction, glial cells, which usually cover the connection between neurons, retract from synaptic regions. The researchers thus decided to compare synaptic transmission and plasticity in hypothalamic slices of brain from lactating and non-lactating rats.
Results proved the model correct–glial cell retraction coincided with a decrease in the amount of D-serine in synapses, and with a reduction in the number of excitable NMDA receptors. Long Term Potentiation (LTP)–the mechanism at the basis of synaptic plasticity, by which synapses are reinforced–was harder to launch and synapses became weaker.
“During lactation, the lack of D-serine makes it difficult for synapses to become stronger,” says Oliet. “Making LTP harder to achieve may in fact be used to favor synapses that are already very active, like those involved in lactation.”
The next step will be to figure out if glia influences synaptic plasticity in the hippocampus, the cerebellum, or the cerebral cortex, which are the classic regions responsible for memory formation and learning processes. If it were the case, new therapeutic paths could be investigated to treat neuronal illnesses such as schizophrenia and Alzheimer's, known to involve dysfunctional NMDA receptors.
1. Morphofunctional Neurobiology lab, Inserm, Bordeaux, in collaboration with the Cellular and Molecular Neurobiology lab, Gif-sur-Yvette, France.
2. Panatier et al., “Glia Derived D-Serine Controls NMDA Receptor Activity and Synaptic Memory,” Cell, 125: 775-784. 2006.
Neurobiologie Morphofonctionnelle, Bordeaux.