The contribution of astrocyte signalling to neurovascular coupling

Abstract

The tight spatial and temporal coupling between neuronal activity and blood flow ensures that active brain regions receive an adequate supply of oxygen and energetic metabolites. There clearly is still an enormous amount of experimental and theoretical work to be done to unravel the precise mechanism of neurovascular coupling, but over the last decade significant advances have been made. The most recent studies confirm the original finding that the activation of Ca²⁺ elevations in astrocyte endfeet is an essential step but also reveal new levels of complexity in the astrocyte control of neurovascular coupling. The recent evidence for a link between Ca²⁺ signalling in astrocytes and local metabolic states of the brain tissue has broad implications for the interpretation of data from functional brain imaging studies. Unraveling the full molecular mechanism of the astrocyte control of cerebral blood flow represents a formidable challenge in neurobiological research in the years to come that might also create opportunities for the development of new therapeutic strategies for cerebrovascular diseases such as ischemic stroke, hypertension and migraine as well as neurodegenerative diseases as Alzheimer's disease.

Introduction

Functional hyperemia is a fundamental phenomenon in normal brain function. First discovered by A. Mosso in the late 1800s (Mosso, 1880), and later confirmed by Roy and Sherrington (1890), functional hyperemia reflects the dilation of arterioles and capillaries of a restricted brain region and perhaps also the constriction of other blood vessels from adjacent and distant regions, in response to a local episode of high neuronal activity. This event is spatially restricted, occurs within a few seconds of the onset of an episode of intense neuronal activity, and it ensures that active neurons can be sustained by adequate amounts of oxygen and metabolic substrates. Initially, the local accumulation of metabolic products was proposed to directly control blood flow, but it soon became clear that the time course of this process was not consistent with the rapid response observed in blood vessels upon increased neuronal activity (Lou et al., 1987). Indeed, results obtained over the last few years provide significant support for the view that CBF is directly coupled to neuronal activity rather than to local energy needs (Attwell and Iadecola, 2002). Although important questions remain unanswered, during the same period our knowledge of the mechanisms at the basis of functional hyperemia has increased significantly revealing not only the contribution of multiple cellular and molecular signalling pathways, but also the central role of neuron-to-astrocyte signalling (Zonta et al., 2003b, Zonta et al., 2003a, Filosa et al., 2004, Mulligan and MacVicar, 2004, Lovick et al., 2005, Metea and Newman, 2006b, Metea and Newman, 2007).

A crucial premise for the identification of the role of astrocytes in functional hyperemia was the discovery that astrocytes can respond to transmitters released by neuronal activity with intracellular Ca²⁺ elevations and signal back to neurons by releasing chemical transmitters (Dani et al., 1992, Nedergaard, 1994, Parpura et al., 1994, Newman, 1995, Porter and McCarthy, 1996, Pasti et al., 1997, Mothet et al., 2000, Mothet et al., 2005), now termed gliotransmitters. These observations promoted an emerging new understanding of the functional roles played by these glial cells in the brain. It is now recognized that astrocytes listen and talk to synapses exerting both excitatory and inhibitory actions on neurons (Araque et al., 1999b, Brockhaus and Deitmer, 2002, Zhang et al., 2003, Pascual et al., 2005, Panatier et al., 2006, Serrano et al., 2006, Jourdain et al., 2007, Perea and Araque, 2007). Astrocytes are now considered intrinsic elements of the neuronal circuit that compose a tripartite synapse with the pre- and post-synaptic neuronal membrane (Araque et al., 1999a, Carmignoto, 2000, Haydon and Carmignoto, 2006, Halassa et al., 2009, Perea et al., 2009).

Beside their role as local modulators of neuronal excitability and synaptic transmission, astrocytes may also serve a hub-like function by integrating the signal received from thousands of synapses and then transferring it to other cells in the neuron-astrocyte network, including the cerebral vasculature that is intimately enwrapped by the astrocytic processes, the so-called endfeet (Peters et al., 1991, Ventura and Harris, 1999, Simard et al., 2003). It is because of this polarized anatomical structure and the vicinity of their endfeet to contractile elements of blood vessels, such as smooth muscle cells in arterioles and pericytes in capillaries, that astrocytes have been long proposed to contribute to the regulation of cerebral blood flow (CBF) during neuronal activity. Additional clues for such a role were the ability of astrocytes to produce and release a number of vasoactive substances, including nitric oxide (NO) (Murphy et al., 1993, Wiencken and Casagrande, 1999, Li et al., 2003), cycloxygenase (COX) and epoxygenase activity-derived products (Pearce et al., 1989, Oomagari et al., 1991, Amruthesh et al., 1992, Amruthesh et al., 1993, Alkayed et al., 1997, Shi et al., 2008) and ATP (Queiroz et al., 1999, Arcuino et al., 2002, Coco et al., 2003). Only recently, however, did a number of studies provide convincing evidence that the neuron-to-astrocyte signalling pathway indeed serves a major role in functional hyperemia, the coupling between local episodes of intense neuronal activities and CBF (Fig. 1).

A number of comprehensive reviews have recently discussed our current understanding of how astrocytes are activated by neuronal signals and release vasoactive agents to regulate vascular tone (Haydon and Carmignoto, 2006, Filosa and Blanco, 2007, Gordon et al., 2007, Iadecola and Nedergaard, 2007, Koehler et al., 2009). We will thus restrict our review to the most recent observations that represent remarkable advances in our understanding of the amazing complexity of this important phenomenon.