Binaural blood flow control by astrocytes: listening to synapses and the vasculature

Abstract

Astrocytes are the most common glial cells in the brain with fine processes and endfeet that intimately contact both neuronal synapses and the cerebral vasculature. They play an important role in mediating neurovascular coupling (NVC) via several astrocytic Ca -dependent signalling pathways such as K release through B channels, and the production and release of arachidonic acid metabolites. They are also involved in maintaining the resting tone of the cerebral vessels by releasing ATP and COX-1 derivatives. Evidence also supports a role for astrocytes in maintaining blood pressure-dependent change in cerebrovascular tone, and perhaps also in blood vessel-to-neuron signalling as posited by the 'hemo-neural hypothesis'. Thus, astrocytes are emerging as new stars in preserving the intricate balance between the high energy demand of active neurons and the supply of oxygen and nutrients from the blood by maintaining both resting blood flow and activity-evoked changes therein. Following neuropathology, astrocytes become reactive and many of their key signalling mechanisms are altered, including those involved in NVC. Furthermore, as they can respond to changes in vascular pressure, cardiovascular diseases might exert previously unknown effects on the central nervous system by altering astrocyte function. This review discusses the role of astrocytes in neurovascular signalling in both physiology and pathology, and the impact of these findings on understanding BOLD-fMRI signals.

The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease

“…Subsequent studies using pharmacological approaches also in brain slices extended these initial observations demonstrating that increases in astrocytic Ca 2+ , triggered by neural activity, photolysis of caged Ca 2+ or activation of mGluR5, have the potential to modulate microvascular diameter, producing constriction or dilatation depending on the oxygen levels (Gordon et al, 2008), resting vascular tone (Blanco et al, 2008) or extracellular K + (Girouard et al, 2010). The postulated sequence of events leading to vasodilation is that glutamate released by synaptic activity activates mGluR on astrocytes leading to inositol 3-phosphate (IP3) mobilization and Ca 2+ release from intracellular stores, phospholipase-A 2 (PLA 2 ) activation, release of arachidonic acid and production of PGE 2 and epoxyeicosatrienoic acids (EETs) via the COX and cytochrome p450 epoxygenase pathways, respectively (Attwell et al, 2010; Mishra, 2016). An alternative mechanism is that Ca 2+ transients in astrocytes activate large conductance Ca 2+ activated K + (BK) channels in astrocytic end-feet leading to K + release and vascular SMC relaxation through K IR channels (Filosa et al, 2006).…”

“…Subsequent in vivo studies challenged the role of astrocytic Ca 2+ transients and attendant upstream and downstream signaling in neurovascular coupling (reviewed in (Mishra, 2016; Petzold and Murthy, 2011; Uhlirova et al, 2016a)). The increases in Ca 2+ may be too slow (Takano et al, 2006), often occurring after the onset of the hemodynamic response (Bonder and McCarthy, 2014; Nizar et al, 2013).…”

SGK3 Sensitivity of Large-Conductance Ca²⁺-Activated K⁺ Channel

“…The channels are activated by increase of cytosolic Ca 2+ activity [20] and are highly sensitive to cell membrane potential [20]. The channel properties are modified by accessory subunits [20,48], BK channel protein abundance and activity could be modified by posttranslational modification including protein phosphorylation, lipidation, glycosylation, and ubiquitination [85][86][87][88][89].…”

“…In neurons [20], BK channels contribute to repolarization and fast afterhyperpolarization of action potentials [52,53] and thus influence dendritic Ca 2+ spikes [54], and neurotransmitter release [55][56][57][58]. They are involved in motor coordination [59], learning and memory [28,[60][61][62], circadian rhythm [63][64][65][66], regulation of respiration [67][68][69], hearing [70], and pain [71][72][73][74].…”

“…At least in theory, SGK3 may similarly modify the large conductance Ca 2+ -activated K + channels (maxi K + channels or BK channels, KCNMA1), which are ubiquitously expressed [20,21] and participate in the tuning of a wide variety of functions including regulation of neuronal excitability , cell volume [45][46][47], vascular tone and blood pressure [48,49], urinary bladder contraction [50], as well as erection [51].…”