Astrocyte functions

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Astrocytes in the hippocampus

by Rachel E. Ventura

Modulating ECS volume fraction through astrocytic swelling and filopodia extension

Astrocytes are an important determinant of the volume fraction of the extracellular space. Astrocytic swelling has been shown to occur as a result of both glutamate and adenosine receptor stimulation (Hansson, 1994; Bourke et al., 1983). Filopodial extension, or outgrowth of membrane, can be induced in astrocytes by focal application of glutamate (Cornell-Bell et. al., 1992). This filopodial extension can change the astrocytic size and morphology, possibly also altering the volume fraction occupied by extracellular space.

Synaptic function is sensitive to the extracellular volume fraction. As the volume fraction decreases, the concentration of components of the extracellular space increases and this could, theoretically, increase a neuron’s responsiveness to a given amount of neurotransmitter inputted. In fact, it has been shown that when the extracellular volume fraction is decreased as a result of increasing the concentration of K+, which is known to induce astrocytic swelling, the excitability of the neurons increases to the extent that seizures result (reviewed in Porter and McCarthy, 1997; Traynelis and Dingledine, 1989). Also, furosemide, which is known to block astrocytic swelling, has been recently shown to prevent electrically induced seizures (Hochman et al., 1995; Porter and McCarthy, 1997). These results suggest that astrocytes, through modulation of their size, can influence the excitability of neurons.

Ion channels, and neurotransmitter receptors

Astrocytes contain a wide variety of ion channels and neurotransmitter receptors and transporters. The K+ and Ca2+ ion channels are used by the astrocytes to maintain brain homeostasis for these ions. During synaptic activity, there is a buildup of K+ in the extracellular space, which is alleviated by astrocytic uptake (Nilsson and Hagberg, 1997). The astrocytes then eject the uptaken K+ into the capillary blood (Nilsson and Hagberg, 1997). The role of astrocytic Ca2+ ion channels is as of yet unclear.

In addition to ion channels, astrocytes contain neurotransmitter receptors. Before 1980 (Van Calker and Hamprecht, 1980), these receptors had only been observed in neurons, and were not thought to occur on astrocytes. The receptor types found in astrocytes are similar to those found in neurons. Among the astrocytic receptors are glutamatergic, GABAergic, adrenergic, serotonergic, and muscarinic receptors, each with differential expression across astrocytes and in different brain regions, and each coupled to a second messenger cascade (reviewed in Kimelberg, 1995; Porter and McCarthy, 1997).

Possibilities for influencing neuronal excitability

In addition to changing cell volume, astrocytes have other ways of modulating neuronal excitability. For example, an astrocytic depolarization near a presynaptic terminal could lead to an increase in the amount of neurotransmitter released (Ronnback and Hansson, 1997). Also, if the transmitter release is Ca2+-dependent, then astrocytic control of the concentration of Ca2+ in the extracellular space would lead to changes in excitability (Ronnback and Hansson, 1997). Other possibilities exist as well. Research has, in fact, shown that developing neurons in culture do not achieve fully functional synapses until glia are introduced (Pfrieger and Barres, 1997), though the mechanism of action for this is not known.

Astroglial glutamate uptake and the possibility of inter-synaptic glutamate spillover

Astrocytes contain high affinity glutamate transporters that are critical in maintaining the extracellular glutamate concentration at sub-excitotoxic levels and thereby preventing neuronal cell death (Rothstein et al., 1994; Rothstein et al., 1996). Insufficient glutamate uptake by the transporters is believed to play a role in amyotrophic lateral sclerosis, Alzheimer’s disease, schizophrenia, and AIDS, to name a few. Astrocytic uptake of glutamate may also serve to fine-tune the time course of glutamate in the synaptic cleft, perhaps by terminating the synaptic signal (Mennerick and Zorumski, 1994). Additionally, astrocytes may mediate inter-synaptic spillover of glutamate.

Depicted above is a hypothetical model explaining why NMDA receptors (N) sense a different number of quanta than AMPA (A) receptors. Dotted line shows the path of glutamate as it escapes from the cleft of synapse 1 and reaches synapse 2. In this model, spillover occurs because there are no astrocytic processes (black) along the path to uptake the relased glutamate. The bouton of synapse 2 (darkened) is releasing little or no glutamate, and therefore the concentration of glutamate that reaches synapse 2 is sufficient only to activate the (high-affinity) NMDA receptors. One problem with this model is that the high levels of extrasynaptic glutamate would lead to a general excitotoxicity.

Since astrocytes contain high enough densities of glutamate transporters to effectively prevent glutamate from diffusing past them, the presence of astrocytes near the synapses may be an important determinant of whether or not spillover occurs. In the hippocampal CA1 area, short inter-synaptic distances have indeed been observed, without any intervening structures to uptake glutamate (Ventura and Harris, 1999). Alternatively, since astrocytes grow towards released glutamate (Cornell-Bell et al., 1990), it is possible that only synapses with astrocytic processes at their axon-spine interface are releasing glutamate.

Depicted above is an alternative model explaining why NMDA receptors (N) sense a different number of quanta than AMPA receptors (A). Synapse 2 in (a) has little or no pre-synaptic release of glutamate and only NMDA receptors post-synaptically. When synapse 2 spontaneously releases quanta of glutamate, the NMDA receptors detect this, while there are no AMPA receptors present to sense the glutamate. The amount of release at synapse 2 in (a) is insufficient to spill over to neighboring synapses, and the astrocytes (black) prevent spill over from the active synapse 1. In (b), astrocytic processes have grown along a concentration gradient of glutamate towards the newly releasing synapse 2. Simultaneously, synapse 2 has recruited AMPA receptors post-synaptically.

This model, the astrocytic growth/AMPA receptor recruitment model, argues against spillover. Instead, it is possible that the discrepancy of the number of quanta sensed by NMDA and AMPA receptors may be explained by recruitment of AMPA receptors to the post-synaptic densities as the synapse becomes active (reviewed in Malenka and Nicoll, 1995).

Last Updated: 8/9/00