2012; Papanastasiou et al. 2013]. Modulation of cortical

networks Linking these well-established actions with a mechanism to explain putative antidepressant effects has proven more difficult. At a more global cortical level, data from healthy subjects have selleck kinase inhibitor demonstrated the concept of two large anticorrelated cortical networks. The so-called default mode network (DMN) is an intrinsic functionally dominant non-goal-orientated resting state, Inhibitors,research,lifescience,medical whilst the extrinsic attentional network is involved in goal-driven behaviour, and the connections between these modular hubs can dysfunction in mental illnesses [Raichle et al. 2001; Tracy and Shergill, 2013]. In depression a so-called ‘dorsal nexus’ comprising the bilateral dorsal medial PFC has been shown to have marked increased functional Inhibitors,research,lifescience,medical connectivity with the DMN [Sheline et al. 2010]. This greater activation of the resting-state non-goal-directed network is associated with introspection and self-reflective processes that can pathologically increase in depression, and the degree of DMN dominance has been

demonstrated to be correlated with the degree of depressive rumination [Hamilton et al. 2011]. Scheidegger and colleagues Inhibitors,research,lifescience,medical showed that in healthy individuals ketamine decreased the connectivity of the DMN to the dorsal nexus and the medial PFC, and the authors argue that the antidepressant effects of

ketamine Inhibitors,research,lifescience,medical might therefore be due to re-regulating illness-induced dysfunctional connectivity, particularly in the limbic–cortico–striato–pallido–thalamic circuits involved in mood [Scheidegger et al 2012]. Effects on neurotransmitters The dominant, albeit incomplete, pharmacological model of depression focuses upon the monoaminergic neurotransmitters serotonin and noradrenaline (and to a far lesser extent dopamine). The therapeutic Inhibitors,research,lifescience,medical actions of current antidepressants are highly Phosphoprotein phosphatase likely to involve complex intracellular enzymatic chains downstream of changes to monoamines, with alterations in neuronal gene transcription [Brown and Tracy, 2013; Penn and Tracy, 2012]. Far less work has explored the role of the ubiquitous excitatory neurotransmitter Glu in depressive disorders: there is reasonably strong evidence to support dysfunction, though not attribute clear causality (for a review, see Sanacora and colleagues [Sanacora et al. 2012]). Extracellular levels of Glu are tightly controlled, as in excess in the synapse it is excitotoxic: after neuronal release it is recycled through glial support cells and enzymatically converted by glutamine synthetase to glutamine, which is then re-uptaken by neurons and hydrolysed back into Glu.