Les lésions anciennes: Evolution conserves noradrenergic regulation of astroglial homeostatic support

It is a truth universally acknowledged that every neurone needs an astrocyte to survive and operate. Supportive, homeostatic, and protective neuroglial cells emerged early in evolution together with the centralised nervous system (although some collateral cells of non-neural origin aiding neurones and axons probably existed in even earlier diffuse nervous system of Cnidarians and Ctenophoa). In the February issue ofActa Physiologica, a team of researchers led by Nina Vardjan and Robert Zorec¹ reveals ancient evolutionary roots of noradrenergic signalling and describes the association with astrocytes, astrocytic Ca²⁺ signalling, and astrocyte physiology.

The very first glial cells were parts of sensory organs, known as sensillas, in invertebrates; incidentally, glial-neuronal sensory organs are common in all species (for example, the organ of Corti, taste buds and olfactory epithelium have ~50% of sustenacular glial cells, which are indispensable for proper sensory function²). The rise of neuroglia reflects the main evolutionary principle of division of functions: neurones are so specialised for the generation of action potentials and synaptic transmission that they cannot sustain the major homeostatic and defensive tasks that define the optimal performance and survival of the nervous tissue. These tasks are fulfilled by neuroglia.³

Astroglial cells, which include many types of parenchymal and radial astrocytes, ependymoglia, and astrocyte-like stem cells, are major homeostatic cells in the central nervous system (CNS) that control and execute various functions at all levels of biological organisation, ranging from molecules to organs. In particular, astrocytes control ion homeostasis of the interstitium (also known as ionostasis) and are the main elements of production, clearance, and catabolism of major neurotransmitters and neuromodulators including L-glutamate, GABA, adenosine, catecholamines, and D-serine.⁴ Astrocytes are electrically non-excitable cells, which employ intercellular ion and second messenger signalling as the substrate of excitability.⁵ Astrocytic ionic signalling is mediated by Ca²⁺, Na⁺, and Cl^{− 6}; the main second messengers are inositol-1,4,5-trisphosphate (InsP₃, linked to Ca²⁺ signalling) and cyclic AMP (cAMP) regulating multiple intracellular enzymatic cascades.⁵ Coordination of ionic and second messenger excitability is critical for astrocytic function in many physiological and pathophysiological contexts.

Noradrenergic innervation of the CNS is mainly associated with the locus coeruleus, the brain stem nucleus containing (in humans) ~20 000–50 000 noradrenergic neurones full of neuromelanin that gives them a dark blue appearance. The locus coeruleus was discovered in 1784 by Félix Vicq-d'Azyr (the last physician of Queen Marie-Antoinette), although the name locus coeruleus was invented by Joseph and Karl Wenzel in 1812, and means the blue spot in Latin. Axons of locus coeruleus neurones project throughout the brain and the spinal cord and deliver the bulk of noradrenaline to the CNS. Noradrenaline is released from multiple varicosities, acting, therefore, as a bona fide volume transmitter. Noradrenergic innervation provided by the locus coeruleus contributes to the widest range of physiological processes, including the sleep–wake cycle, arousal, attention, learning and memory, brain metabolism, and many more. Noradrenergic transmission is also a critical element of the stress response.^{7, 8} Astrocytes are the main target for noradrenaline in the CNS; noradrenaline triggers both Ca²⁺ (through α₁ adrenoceptors) and cAMP (through α₂ and β-adrenoceptors) signalling.^{9, 10} These signals in turn translate into multiple astrocytic responses—they regulate astrocytic morphology, energy metabolism, formation of lipid droplets, activity of pumps and transporters, and secretion of various molecules that signal to neurones and other cells of the nervous tissue.

In the recent Acta Physiologica publication, Cerne et al.¹ studied monoaminergic excitation and Ca²⁺signalling in astrocytes in Drosophila melanogaster. These fruit flies have highly elaborated neuroglia, and a quite complex CNS, which was already noticed by Santiago Ramon y Cajal (1852–1934), who praised insects because they “possesses an extremely complex and differentiated nervous system”.¹¹ Neuroglia in Drosophila is not very numerous (~10 000 cells accounting for ~10% of all cells in the nervous system) but remarkably heterogeneous.¹² Over 30 different specialised neuroglial types were indentified and grouped into four major subclasses: (i) surface glia (perineural and subperineural glia) that form the barrier separating the nervous system from the haemolymph and the rest of the body, (ii) cell body glia or cortex glia that are covering neuronal somata, (iii) neuropil glia (including astrocyte-like cells), which ensheath and interact with synapses and populate neuropil, and (iv) periaxonal glia (also known as nerve-cord glia).¹²

Despite a huge evolutionary gap, the brain of Drosophila, similar to humans, receives widely distributed monoaminergic innervation, in which octopamine and tyramine act as neurotransmitters.¹ Again, as in humans, the monoaminergic system regulates multiple processes, including metabolism, learning and memory, the fight-or-flight (i.e., stress) response, and the sleep–wake cycle (Figure 1). Neurones and neuroglia of the Drosophila CNS express receptors to both neurotransmitters (Octopamine: OctRs, Octα_1-2Rs, and Octβ_1-3Rs; Tyramine: Tyr_1-3Rs). Octopamine receptors trigger Ca²⁺ signalling in both cell types; however, the sensitivity of neuroglial receptors is much higher: the EC₅₀ of neuroglial OctRs was found to be six times lower than neuronal ones.¹

To summarize, the monoaminergic system innervating the brain shows remarkable evolutionary conservation—it acts mainly through astroglia, by virtue of merely two types of receptors connected to ionic and second messenger signalling, and thus controls the most fundamental brain functions.