Astrocytes in rapid ketamine antidepressant action
Matjaž Stenovec, Baoman Li, Alexei Verkhratsky, Robert Zorec
Neuropharmacology, 2020, 173, 108158
Doi : 10.1016/j.neuropharm.2020.108158
H I G H L I G H T S
• Ketamine inhibits calcium signalling and enhances cAMP production in astroglia.
• Ketamine suppresses exocytosis of gliosignalling molecules and Kir4.1.
• Ketamine elevates cholesterol content in the plasmalemma specifically in astrocytes.
A B S T R A C T
Ketamine, a general anaesthetic and psychotomimetic drug, exerts rapid, potent and long-lasting antidepressant effect, albeit the cellular and molecular mechanisms of this action are yet to be discovered. Besides targeting neuronal NMDARs fundamental for synaptic transmission, ketamine affects the function of astroglia the key homeostatic cells of the central nervous system that contribute to pathophysiology of psychiatric diseases including depression. Here we review studies revealing that (sub)anaesthetic doses of ketamine elevate intracellular cAMP concentration ([cAMP]i) in astrocytes, attenuate stimulus-evoked astrocyte calcium signalling, which regulates exocytotic secretion of gliosignalling molecules, and stabilize the vesicle fusion pore in a narrow configuration possibly hindering cargo discharge or vesicle recycling. Next we discuss how ketamine affects astroglial capacity to control extracellular K+ by reducing cytoplasmic mobility of vesicles delivering the inward rectifying potassium channel (Kir4.1) to the plasmalemma. Modified astroglial K+ buffering impacts upon neuronal excitability as demonstrated in the lateral habenula rat model of depression. Finally, we highlight the recent discovery that ketamine rapidly redistributes cholesterol in the plasmalemma of astrocytes, but not in fibroblasts nor in neuronal cells. This alteration of membrane structure may modulate a host of processes that synergistically contribute to ketamine’s rapid and prominent antidepressant action.
Keywords : Astroglia, Ketamine, Cytosolic excitability, Exocytosis, Potassium homeostasis, Cholesterol
1. Astrocytes, the keepers of the nervous tissue
From the very dawn of evolution the cellular elements of the nervous system were separated into electrically excitable neurones that represent the executive arm responsible for information processing and decision making and neuroglia, which provided homeostatic support for nervous tissue. The very first glial cells emerged with transition from diffuse nervous system operational in Cnidarians and Ctenophores to centralised nervous system in which compact neuronal masses (ganglia and neuronal rings) were formed (Hartline, 2011; Verkhratsky et al., 2019). Ancestral supportive glia found in earthworms and flatworms are represented by several subtypes (Csoknya et al., 2012; Sukhdeo and Sukhdeo, 1994), associated either with peripheral nerves (neurilemmal-, subneurilemmal- and periaxonal sheath-forming glia), or with neuronal somata (supporting-nutrifying-glia). Another type of primordial glia evolved in round worms; in Caenorhabditis elegans the main glial function was in forming peripheral sensory organs, sensillas.
Each sensilla was formed by socket and sheath glial cells supporting neuronal terminals (Oikonomou and Shaham, 2011). This glio-neuronal sensory organs have been conserved and are present in mammals in taste buds, in olfactory epithelium and in recently discovered subcutaneous sensory organs formed by nociceptive Schwann cells and terminals nociceptive axons (Abdo et al., 2019; Gravina et al., 2013; Hegg et al., 2009; Tang et al., 2019). Supportive neuroglial cells of the central nervous system (CNS) underwent remarkable diversification in evolution ultimately developing into parenchymal homeostatic cells or astrocytes, axon supportive myelinating oligodendrocytes and defensive microglia (Verkhratsky and Butt, 2013; Verkhratsky and Nedergaard, 2016). Astrocytes, are principal homoeostatic cells of the brain and of the spinal cord, which account (depending on the region), for 20–40% of the entire glial cell population in the human brain, and represent the major glial population in the human spinal cord (Azevedo et al., 2009; Ben Haim and Rowitch, 2017; Herculano-Houzel, 2014; Khakh and Sofroniew, 2015; Oberheim et al., 2012; Verkhratsky and Butt, 2018; Verkhratsky and Nedergaard, 2018; Verkhratsky et al., 2012b). Astrocytes maintain CNS homoeostasis at all levels of organization, from molecular to the whole organ, and provide for defence of the CNS through evolutionary conserved programme of reactive astrogliosis (Verkhratsky and Nedergaard, 2018; Verkhratsky et al., 2017). During brain development, astrocytes (in the form of radial glia) generate neural progenitors and guide migrating neurones towards their destinations in the neocortex, and instruct them to form synapses that connect functional neuronal networks (Ullian et al., 2001). In the adult brain, astrocytes signal back to neurones by secreting gliosignalling molecules (Verkhratsky et al., 2016; Zorec et al., 2016) and other factors that regulate the strength of synapses essential for learning and memory formation (Clarke and Barres, 2013; Zorec et al., 2015). Astrocytes promote the survival of existing neurones (Seri et al., 2001).
The perceived importance of astrocytes has provided a new momentum to an old idea of astrocytes playing a key role in pathogenesis of neurological diseases including neurodegenerative disorders such as Alzheimer’s disease (AD), Huntington disease (HD), Parkinson disease and amyotrophic lateral sclerosis (ALS), and neuropsychiatric disorders.
Indeed, rapidly mounting evidence indicates that malfunction of astrocytes underlies many, if not all, neurological, neuropsychiatric and neurodegenerative disorders (Pekny et al., 2016; Verkhratsky et al., 2017). Therefore, astrocytes represent, a therapeutic target, and many of the neurological drugs already in use, achieve their beneficial effects through astrocytes (Trkov Bobnar et al., 2019).
2. Astroglial face of mood disorders
The association between astrocytes and psychiatric disorders such as schizophrenia, bipolar disorder or major depressive disorder (MDD) is well documented (Dietz et al., 2019; Peng et al., 2016; Rajkowska and Stockmeier, 2013; Verkhratsky and Nedergaard, 2014). Since astrocytes stabilize the environment for neuronal networks and provide growth factors, functional deficiency of astrocytes could destabilise operation of neural circuits in the brain areas involved in mood regulation. Of note, astrocytes control the amount of glutamate at synapses, and abnormalities in its levels have been linked to a variety of psychiatric disorders, including depression, anxiety, and schizophrenia (Holden, 2003). In addition, astrocytes recycle different neurotransmitters implicated in psychiatric disorders, such as serotonin, dopamine, and other monoamines.
In contrast to other neuropathologies, psychiatric disorders and MDD in particular are characterised with prevalence of astroglial atrophy and degeneration without signs of reactivity (Tables 1 and 2 (Rajkowska and Stockmeier, 2013; Verkhratsky et al., 2014);). Reduction in the packing density or number of Nissl-stained populations of astrocytes in individuals diagnosed with major depressive disorder (MDD) as compared to non-psychiatric controls have been frequently reported (Bowley et al., 2002; Cotter et al., 2001, 2002; Gittins and Harrison, 2011; Ongur et al., 1998; Rajkowska et al., 1999). These changes were observed in fronto-limbic brain regions including the dorsolateral prefrontal cortex (Cotter et al., 2002; Rajkowska et al., 1999), orbitofrontal cortex (Rajkowska et al., 1999), subgenual cortex (Ongur et al., 1998), anterior cingulate cortex (Cotter et al., 2001; Gittins and Harrison, 2011), and amygdala (Bowley et al., 2002). The density of astrocytes and area fraction of glial fibrillary acidic protein (GFAP)-positive profiles were substantially reduced in the white matter of post-mortem human tissues and in rats subjected to chronic stress (Rajkowska and Stockmeier, 2013). Likewise the GFAP expression and density of astrocytes was reduced in the grey matter of rodents displaying depressive-like phenotypes following exposure to various types of stress (Braun et al., 2009; Czeh et al., 2006). Animal models of attention deficit disorder and MDD also demonstrated down-regulation of other classical astroglial markers such as aquaporin 4, astroglia-specific connexins, astroglial plasmalemmal glutamate transporters and glutamine synthetase (Barley et al., 2009; Bernard et al., 2011; Sequeira et al., 2009). Pharmacological inhibition of astroglial gap junctional connectivity (Sun et al., 2012) as well as astroglial glutamate transporters (Bechtholt-Gompf et al., 2010) triggered anhedonia (suggestive of depressive phenotype). Artificial ablation of astrocytes following injection of gliotoxin L-α-aminoadipic acid into the medial-prefrontal cortex of mice instigated depression-like phenotypes (Banasr and Duman, 2008).
3. Astrocytes as targets for anti-depressant therapies
Pharmacological experiments performed during recent decade clearly demonstrated that treatment with classic antidepressants (such as fluoxetine, Li+ or valproic acid) affect numerous signalling cascades present specifically in astroglia; in particular these medicines modify expression of a variety of receptors and transporters responsible for CNS homeostasis and support of synaptic transmission (Table 2 and (Czeh and Di Benedetto, 2013; Dong et al., 2015; Liu et al., 2015; Peng et al., 2018; Rivera and Butt, 2019)).
Serotonin specific reuptake inhibitors (SSRI), which include fluoxetine, paroxetine, citalopram, fluovoxanine and sertraline in particular, were found to specifically interact with astroglial serotonin 5-HT2B receptors (Zhang et al., 2010). The SSRIs, of which fluoxetine is the most studied, were shown to act as specific agonist of astroglial 5-HT2B receptors; stimulation of the latter trigger Ca2+ signalling (Schipke et al., 2011) and transactivation of EGF receptor linked to MAPK/ERK and PI3K/AKT signalling cascades with subsequent modulation of multiple astroglial homeostatic pathways such as glucose metabolism, expression of glutamate transporters, activity of Na+-H+ exchanger, astroglial secretion and many more (Hertz et al., 2012, 2015; Liu et al., 2015; Peng et al., 2018; Ren et al., 2015).