lecture 16.docx

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Department
Cell and Systems Biology
Course
CSB332H1
Professor
Francis Bambico
Semester
Winter

Description
 Recap: rapid anti-depressant treatment including ketamine and DBS  This slide shows excitatory post syn currents on the post syn pyramidal neuron in response to administration of ketamine in comparison to control  Measuring the amount of current/ions that goes into the neuron in a patch clamp experiment  This is a whole cell patch clamp  Patch electrode impales the neuron  Able to quantify the total current going into the neuron in response to diff stimulations  In this case, they quantified 5HT currents  First applied 5HT in bath solution to be able to open all 5HT activated channels/receptors  2 examples of 5HT receptors;  1 is permeable to Na current; open -> fast rapid influx of Na  Also g-protein coupled receptors activated by serotonin; also induce increases in diff types of ionic currents (inward)  Measured this in response to ketamine; all channels associated with serotonin opened and they measured excitatory post syn current and they saw that in comparison to control, without ketamine, the amount of current going into the neuron is dramatically increased -> a lot of inward deflections -> a lot of ions are going into the cell  What does this indicate in terms of effects of ketamine? That compared to control, might indicate that there’s a dramatic increase of 5HT receptors or ions channels associated with 5HT; there might be more 5HT-3 receptors -> more in response of serotonin application -> more current -> more synapses in the neuron;  Functional effect of ketamine; electrophysiological indication that ketamine causes an increase in synaptogenesis -> putative mechanism   Another experiment  Also did whole cell patch clamp recording  But they weren’t looking at synaptic transmission or transmission in response activation of receptors by ligands, serotonin etc  Not looking at transmission that is induced by AP propagating pre syn to activate post  Looking at a transmission independent of AP and this type of transmission is called miniature synaptic transmission  Produced by leak of transmitters into the synaptic cleft; continuous leak without AP causing it  So they were looking at pyramidal neurons, glutamergic transmission  This is a recording of these miniature transmissions in post syn neuron  Can see that the presynaptic neuron is at rest at -70 mV  But you can see changes in post syn current in the post syn neuron -> indication that glutamate are still getting out into the synapse and activating glutamergic receptors  After ketamine, conc on the boxes; you can eliminate these mini post synaptic current  So ketamines action here is the blockage of miniature glutamate synaptic receptors  These researchers have uncovered 1 potential function of mini post syn transmission and that function is related to protein synthesis  They argue that mini results in NMDAR activation in post syn neurons (glut receptors) and spontaneous activation of NMDAR -> activation of this kinase, eEF2 -> phosphorylates its effector and function is to inhibit protein synthesis of many proteins  Important mechanism -> without it, too much glut; uncontrolled -> cancer  So an adapted function  What does ketamine do? it blocks mini transmission and It blocks NMDAR on the post syn neuron, the target of mini -> Inactivation of these pathways -> opp effect -> disinhibit translation -> increase translation of BDNF and additional synaptic protein  BDNF is a growth factor important for the repair of damaged neuronal components, stimulation of growth, formation of synapses, axogenesis  Ketamine through this mechanism also increase synaptogenesis -> the researchers think that it’s associated with the fast anti-depressant effects  Don’t have any answers on the side effects   Proposed pathway  Summary of proposed effects of ketamine  One pathway that blocks mini (hippocampus)  The other activates mTOR  Go over the summary    DBS might also stimulate and produce very fast anti-depressant effects  Important for those at risk for suicide  DBS targets subgenual cortex, just below corpus callosum  Effects of DBS compared to other treatments  rTMS uses electromagnetic pulses; magnetic fields; noninvasive; coil that produces a magnetic field and you just place it on top of the head cause the magn
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