Role of Astrocytes in Matching Blood Flow to Neuronal Activity

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The brain is critically dependent on oxygen and glucose supply for normal function. Various neurovascular control mechanisms assure that the blood supply of the brain is adequate to meet the energy needs of its components. Emerging evidence shows that neuronal activity can control microcirculation using astrocytes as a mediator.

Astrocytes can sense neuronal activity and are involved in signal transmission. Synaptic activity triggers an increase in the intracellular calcium concentration [Ca2+]i of adjacent astrocytes, stimulating the release of adenosine triphosphate (ATP) and glutamate. The released ATP mediates the propagation of Ca2+ waves between neighboring astrocytes, thereby recruiting them to mediate adequate cerebrovascular response to neuronal activation. Simultaneously, sodium‐dependent glutamate uptake in astrocytes generates Na+ waves and subsequently increases glucose uptake and metabolism that leads to the formation of lactate, which is then delivered to neurons as an energy substrate. Further, astrocytic Ca2+ elevations can lead to secretion of vasodilatory substances from perivascular endfeet, such as epoxyeicosatrienoic acid (EETs), adenosine, nitric oxide (NO), and cyclooxygenase‐2 (COX‐2) metabolites, resulting in increased local blood flow. Thus, astrocytes by releasing vasoactive molecules mediate the neuron‐astrocyte‐endothelial signaling pathway and play a profound role in coupling blood flow to neuronal activity.

Introduction

Glial cells were originally described by Virchow (1846) as nonneuronal cells constituting the “glue” of the brain. Later studies classified glial cells in the central nervous system (CNS) as astrocytes, oligodendrocytes, and microglia, each of which has different histological characteristics and functions (Ramon y Cayal, 1911). Once thought to be merely supportive elements, maybe due to the fact that they are nonexcitable cells, glial cells have made the big leap toward the “stars of the show” (Hertz and Zielke, 2004). The big part of the change in their status can be attributed to the findings that glia can integrate neuronal inputs and modulate synaptic activity. In addition, astrocytes can also maintain milieu around the active neurons by regulating extracellular K+ concentration, volume, osmolarity, pH, and concentration of neurotransmitters, particularly glutamate and γ‐aminobutyric acid (GABA) at the synaptic cleft.

Astrocytes are in close association with neurons, can enwrap synaptic terminals (Ventura and Harris, 1999), and have foot processes ensheathing the capillaries. Because of their anatomical location, they were thought for a long time to have an intermediary role in matching neuronal activity to cerebral blood flow (CBF) and metabolism. When neurons in specific brain regions are highly activated, blood flow increases in a temporally and spatially coordinated manner. This coupling between neuronal activity and blood flow, termed functional hyperemia, was first described by Mosso (1880) and confirmed by Roy and Scherrington (1890). As a consequence of neuronal activation blood flow increases in the active area within seconds and thus ensures adequate supply of oxygen and glucose.

This tight coupling between neuronal activity, metabolism, and blood flow has provided the basis for functional brain imaging techniques. Positron emission tomography (PET) uses the coupling between synaptic activity and glucose utility, while functional magnetic resonance imaging (fMRI) is based on the fact that the change in neuronal activity produces variations in the level of hemoglobin oxygenation (Seiyama et al., 2004). The cellular mechanisms of neurovascular coupling have recently been defined and continue to be investigated (Harder 1998, Harder 2000, Harder 2002, Metea 2006). Our group has contributed over the last 10 years to the understanding of such cellular and molecular mechanisms (see Section IV.B.5).

Section snippets

Neurovascular Unit

In 1885, Golgi first described the contact of astrocytic foot processes with arterioles and capillaries (Golgi, 1885). By sending specialized processes to both the vasculature and synaptic contacts, astrocytes have a unique anatomical position between neurons and arterioles to couple neuronal activity to blood supply.

Astrocytes are small cells characterized by small somata (<10 μm) and numerous highly branched processes. The astrocytic process is in close contact with both pre‐ and postsynaptic

Ca2+ Signaling in Astrocytes

Neurons form neuronal networks via synapses while astrocytes form syncytium‐like organizations via gap junctions. Gap junctions are hemichannels that allow the passage of small molecules between cytoplasm of adjacent cells. The major constituent of these hemichannels is connexin 43. These hemichannels have low open permeability in physiological states, but some conditions can change permeability such as an increase in extracellular K+ and low extracellular Ca2+ (Giaume and McCarthy, 1996).

Role of Astrocytic Ca2+ Elevations in Coupling Neuronal Activity to the Vasculature

Because of the anatomical position and the vicinity of foot processes to contractile elements in blood vessels, astrocytes have long been thought to marginally contribute to the regulation of CBF. Studies over the past few years show that synaptic activity, and not the energy deficit due to glucose or oxygen use, is the trigger for neuronal activity‐dependent vasodilation (Sandor, 1999).

Significant evidence supporting a role of astrocytes in regulation of CBF comes from the brain slice

Summary

Astrocytes are no longer regarded as just supportive structures among the brain cells, but play multiple roles in neuronal energy metabolism, synaptic function, pH, water homeostasis, and production of antioxidants in the brain. Despite a growing number of studies confirming the role of astrocytes in neurovascular coupling, the mechanism is still not fully understood. It is now clear that neuronal activity induced Ca2+ elevations and Ca2+ waves are spreading between neighboring astrocytes

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