The NMDA receptor
One key element in LTP is a particular subtype of glutamate receptor, the NMDA receptor. Calcium entry into the cell is one of the triggers for the development of LTP. The NMDA receptor controls a calcium ion channel that is both transmitter dependent and voltage dependent. This means that even when the NMDA receptor is activated by glutamate, no calcium will pass into a cell through the NMDA-controlled channel unless the target cell has also recently been depolarized. So NMDA dependent LTP can only develop in a cell that has been depolarized and then receives a further input – exactly the conditions that apply during a burst of high frequency stimulation. The mechanism underlying this dual sensitivity to neurotransmitter levels and voltage levels is remarkably simple. It turns out that in cells at their normal resting potential, a positively charged magnesium ion is held in the channel by the electrostatic gradient across the cell membrane. If the NMDA receptor is activated, so that the channel could, in principle, be opened, the inflow of calcium is blocked by the magnesium ion. Once the cell is depolarized, nothing holds the magnesium ion in place, so it can diffuse into the extracellular fluid. If the NMDA receptor is again activated at this point, the ion channel opens and, with the magnesium block removed, calcium can pour into the cell, triggering the series of events that leads to LTP. Of course, as the cell repolarizes, the magnesium ion is drawn back into position once more. The LTP system, particularly in the hippocampus, has been a focus of intense research activity. Rat experiments have shown the blockade of the NMDA receptor by the drug AP5 prevents the development of LTP, and at the same time appears to prevent the normal operation of hippocampus-dependent spatial memory (Morris et al., 1986). More recently still, psychological studies of ‘knockout’ mice, genetically engineered so they can no longer show LTP in the hippocampus, have also shown striking failures of hippocampus-dependent spatial memory tasks, that neatly parallel the effects on LTP (e.g. Reisel et al., 2002). If we can combine these new techniques in molecular biology with sophisticated behavioural analysis, we will have ways to study the relation between brain and cognition at a finer level of detail than has ever been possible before. So we have seen that the adult nervous system is highly modifiable: our brains change in accordance with our experiences. Is the development of our brains modified by the environment too?
One key element in LTP is a particular subtype of glutamate receptor, the NMDA receptor. Calcium entry into the cell is one of the triggers for the development of LTP. The NMDA receptor controls a calcium ion channel that is both transmitter dependent and voltage dependent. This means that even when the NMDA receptor is activated by glutamate, no calcium will pass into a cell through the NMDA-controlled channel unless the target cell has also recently been depolarized. So NMDA dependent LTP can only develop in a cell that has been depolarized and then receives a further input – exactly the conditions that apply during a burst of high frequency stimulation. The mechanism underlying this dual sensitivity to neurotransmitter levels and voltage levels is remarkably simple. It turns out that in cells at their normal resting potential, a positively charged magnesium ion is held in the channel by the electrostatic gradient across the cell membrane. If the NMDA receptor is activated, so that the channel could, in principle, be opened, the inflow of calcium is blocked by the magnesium ion. Once the cell is depolarized, nothing holds the magnesium ion in place, so it can diffuse into the extracellular fluid. If the NMDA receptor is again activated at this point, the ion channel opens and, with the magnesium block removed, calcium can pour into the cell, triggering the series of events that leads to LTP. Of course, as the cell repolarizes, the magnesium ion is drawn back into position once more. The LTP system, particularly in the hippocampus, has been a focus of intense research activity. Rat experiments have shown the blockade of the NMDA receptor by the drug AP5 prevents the development of LTP, and at the same time appears to prevent the normal operation of hippocampus-dependent spatial memory (Morris et al., 1986). More recently still, psychological studies of ‘knockout’ mice, genetically engineered so they can no longer show LTP in the hippocampus, have also shown striking failures of hippocampus-dependent spatial memory tasks, that neatly parallel the effects on LTP (e.g. Reisel et al., 2002). If we can combine these new techniques in molecular biology with sophisticated behavioural analysis, we will have ways to study the relation between brain and cognition at a finer level of detail than has ever been possible before. So we have seen that the adult nervous system is highly modifiable: our brains change in accordance with our experiences. Is the development of our brains modified by the environment too?
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