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University of Toronto St. George
Cell and Systems Biology
Francis Bambico

 Recap: ketamine has been found to induce very fast anti-dep effects o Associated with rapid synaptic genesis, particularly in prefrontal cortex o Mediated by mTOR -> increase in translation  Argument by one paper: found diff effects of ketamine o Weren’t able to replicate the activation of mTOR by ketamine o Found phosphorylation of another protein in the hippocampus -> responsible for memory and motor processing o This protein is called eEF2 -> a kinase is important in translational machinery  The action of ketamine is independent of mTOR  Ketamine eventually leads downstream to the phosphorylation of this kinase -> inhibit this activity -> inhibiting protein synthesis  Not mTOR but eEF2  Upstream mechanism? We know ketamine is an NMDAR receptor antagonist so what ketamine does is it blocks NMDAR activity -> reducing Ca influx -> series of biochemical pathways leading to phosphorylation of the protein kinase  This transmission is via electrophysio process that is independent of AP firing in the pre synaptic neuron  Even if the pre syn is not firing, neurotransmitters, particularly glutamate in the hippocampus, are constantly being released or leaking out of pre syn  This leakage is referred to -> mini spontaneous post synaptic transmission -> ongoing leakage of glutamate into the synapse without any action potential  This leakage would constantly activate NMDAR -> small amounts of Ca getting into post synaptic neuron -> constant activity of the kinase  When this is blocked, protein kinase is blocked too  Mode of thinking in depressed indiv  Your attention is drawn in your inner world  You overanalyze yourself  Tell yourself you’re worthless  And what ifs and ruminate over the problem, magnify the consequences  After that episode, we tend to forget and focus on resolving the problem  Clinically depressed people can’t get themselves out of this mode of thinking  This process has been associated to hyperactivity of a group of structures in the interior part of the brain that makes up a network called the default mode network  Consists of medial internal structures such as cingulate gyrus, medial prefrontal cortex, subgenual cortex, medial aspect of temporal lobe  Even the brain, in terms of emotions, is topographically mapped so that the inner structures, medially, represents to our emotional response to ourselves and the lateral structures including primary cortices and somatosensory represent our relationship with the outside world  These medial structures are hyperactive in depressed people -> high metabolic activity -> related to chronic stress  Chronic stress induces release of stress hormones, glucocorticoids -> degeneration of synapses in many neurons in the prefrontal cortex -> remaining neurons try to compensate for this loss -> hyperactivity  Experimental procedure - to change the activity of certain regions in the default mode network  One way is to directly intervene with the activity – deep brains stimula
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