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October 19, 2008

LTP Ensures That Memories Are Forever

ResearchBlogging.orgLTP or Long term potentiation is a process that may explain how memory gets stored in the brain for long term use. When you stimulate the presynaptic neuron by giving a brief (of transient duration) but rapid train of stimulus, the post synaptic neuron adjusts its ‘weight of association’ with respects to the presynaptic one, in the form of a chemical reaction. Though LTP occurs throughout the brain, it has been studied mostly in the hippocampus. If we are to understand the underlying molecular mechanism of memory, we can not do without LTP.

Two different types of LTP are known: mossy fiber LTP and Schaffer collateral type LTP. While the basis of mossy fiber LTP is not clearly known; it involves modification of the presynaptic terminal, and is independent of NMDA. A schematic and functional diagram for Schaffer collateral LTP is presented here. But before that, allow me to digress a little bit.

Your computer has a DRAM (Dynamic Random Access Memory) memory chip: memory because it can store and retrieve information; Random access as it allows you to search anywhere within the memory at random (it does not have to reach D via A through B, and then through C, sequentially), and dynamic, since the memory needs to be refreshed from time to time. To store a bit of data in memory, your computer charges devices called ‘capacitors’ within the chip, which retain their charge; and all your computer have to do is to read the data in the form of those stored charges for later retrieval. But these capacitors lose their charge over time and hence dynamic refreshing is necessary to maintain their memory.

You’ll now understand why this digital analogy as we discuss LTP. Schaffer collateral in hippocampus for LTP and synaptic plasticityThe picture on the left portrays a presynaptic neuron which discharges glutamate, the main excitatory neurotransmitter of the brain and the spinal cord. Glutamate after being released upon the stimulation of the presynaptic terminal, binds with their ‘receptors’ in the postsynaptic neuron. The post synaptic neuron, downstream, has 2 types of Glutamate receptors: NMDA (N methyl D Aspartate) and AMPA (alpha Amino 3 hydroxy 5 Methyl isoxazole 4 Propionate). Glutamate binds with both NMDA and AMPA receptors. NMDA receptors have a Magnesium ion, guarding at its channel entry. So, for NMDA receptors to act, it needs to be partially depolarized first, so that this magnesium block is removed. This is achieved by the AMPA receptors, which upon binding with glutamate, allows the entry of Sodium ions inside, thereby raising the cell voltage. NMDA receptors now swing into action as it now allows huge amounts of Calcium ions (and Sodium ions) to enter inside.

These Ca++ then bind with Calmodulin present within the cell to form a complex, which then activates calcium-calmodulin kinase 2 (Ca/Cam k2). This newly formed compound then activates (phosphorylates) AMPA receptors, resulting in: 1) increased activity conductance of the already existing AMPA receptors in the cell membrane 2) Recruitment of AMPA receptors from within the cell to the cell membrane. So we can see that the synaptic strength is increased with each firing by both AMPA recruitment and increased AMPA conductance. The synapse stops at not only this, the postsynaptic neuron also discharges a ‘diffusible’ messenger, nitric oxide (NO), which 'tells' the presynaptic neuron to discharge more quantal release of glutamate next time. The phenomenon epitomizes Hebbian learning: Cells that fire together, wire together.

But the memories so formed need to be stabilized as in the case of DRAM. In the central nervous system, dendritic spines are the main postsynaptic sites. These tiny protrusions form and change over a few hours. In hippocampal slice cultures it was shown, by De Roo and colleagues, that application of theta burst remodeled the dendritic spines; unused ones were shed (trimmed) while used ones were stabilized and new spines were formed. LTP was the chemical basis of all these modifications. They used GFP or green fluorescent protein for visualizing these changes of neural plasticity. However, they (physical units of memory) can also be seen by restorative deconvolution microscopy, in the form of flattened synapses (as if the ohmic resistance getting diminished in their electronic cousins) and hence more area for contact between the pre and postsynaptic neurons. So like DRAM chips, our memory chips too need to be constantly refreshed, even long term memories need maintenance.

Last modified: Jun 26, 2010
Reference:Dominique Muller, Morgan Sheng, Mathias De Roo, Paul Klauser, & Morgan Sheng (2008). LTP Promotes a Selective Long-Term Stabilization and Clustering of Dendritic Spines PLoS Biology

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