Chronic SSRI stimulation of astrocytic 5-HT2B receptors change multiple gene expressions/editings and metabolism of glutamate, glucose and glycogen: a potential paradigm shift

It is firmly believed that the mechanism of action of SSRIs in major depression is to inhibit the serotonin transporter, SERT, and increase extracellular concentration of serotonin. However, this undisputed observation does not prove that SERT inhibition is the mechanism, let alone the only mechanism, by which SSRI’s exert their therapeutic effects. It has recently been demonstrated that 5-HT2B receptor stimulation is needed for the antidepressant effect of fluoxetine in vivo. The ability of all 5 currently used SSRIs to stimulate the 5-HT2B receptor equipotentially incultured astrocyteshas been known for several years,and increasing evidence has shown the importance of astrocytes and astrocyte-neuronal interactions for neuroplasticity and complex brain activity. This paper reviews acute and chronic effects of 5-HT2B receptor stimulation in cultured astrocytes and in astrocytes freshly isolated from brains of mice treated with fluoxetine for 14 daystogether with effects ofanti-depressant therapy on turnover of glutamate and GABA and metabolism of glucose and glycogen. It is suggested that these events are causally related to the mechanism of action of SSRIs and of interest for development of newer antidepressant drugs

Astrocytic and neuronal accumulation of elevated extracellular K+ with a 2/3 K+/Na+ flux ratio - consequences for energy metabolism, osmolarity and higher brain function

Brain excitation increases neuronal Na+ concentration by 2 major mechanisms: i) Na+influx caused by glutamatergic synaptic activity; and ii) action-potential-mediateddepolarization by Na+ influx followed by repolarizating K+ efflux, increasingextracellular K+ concentration. This review deals mainly with the latter and it concludesthat clearance of extracellular K+ is initially mainly effectuated by Na+,K+-ATPasemediatedK+ uptake into astrocytes, at K+ concentrations above ~10 mM aided by uptakeof Na+, K+ and 2 Cl- by the cotransporter NKCC1. Since operation of the astrocytic Na+,K+-ATPase requires K+-dependent glycogenolysis for stimulation of the intracellularATPase site, it ceases after normalization of extracellular K+ concentration. This allowsK+ release via the inward rectifying K+ channel Kir1.4, perhaps after trans-astrocyticconnexin- and/or pannexin-mediated K+ transfer, which would be a key candidate fordetermination by synchronization-based computational analysis and may have signalingeffects. Spatially dispersed K+ release would have little effect on extracellular K+concentration and allow K+ accumulation by the less powerful neuronal Na+,K+-ATPase,which is not stimulated by increases in extracellular K+. Since the Na+,K+-ATPaseexchanges 3 Na+ with 2 K+, it creates extracellular hypertonicity and cell shrinkage.Hypertonicity also stimulates NKCC1, which, aided by -adrenergic stimulation of theNa+,K+-ATPase, causes regulatory volume increase, furosemide-inhibited undershoot in[K+]e and perhaps facilitation of the termination of slow neuronal hyperpolarization(sAHP), with behavioral consequences. The ion transport processes involved minimizeionic disequilibria caused by the asymmetric Na+,K+-ATPase fluxes

Brain Glycogenolysis, Adrenoceptors, Pyruvate Carboxylase, Na+,K+-ATPase and Marie E. Gibbs’ Pioneering Learning Studies

The involvement of glycogenolysis, occurring in astrocytes but not in neurons, in learning is undisputed (Duran et al., JCBFM, in press). According to one school of thought the role of astrocytes for learning is restricted to supply of substrate for neuronal oxidative metabolism. The present ‘perspective’ suggests a more comprehensive and complex role, made possible by lack of glycogen degradation, unless specifically induced by either i) activation of astrocytic receptors, perhaps especially beta-adrenergic, or ii) even small increases in extracellular K+ concentration above its normal resting level. It discusses i) the known importance of glycogenolysis for glutamate formation, requiring pyruvate carboxylation; ii) the established role of K+-stimulated glycogenolysis for K+ uptake in cultured astrocytes, which probably indicates that astrocytes are an integral part of cellular K+ homeostasis in the brain in vivo; and iii) the plausible role of transmitter-induced glycogenolysis, stimulating Na+,K+-ATPase/NKCC1 activity and thereby contributing both to the post-excitatory undershoot in extracellular K+ concentration and the memory-enhancing effect of transmitter-mediated reduction of slow neuronal afterhyperpolarization (sAHP)