By Chris Jung
The ability to store memories and build on them is a key proponent of mammalian life: one that certainly served our early ancestors well and is a fundamental aspect of learning. This stems from synaptic plasticity: a neuron’s ability to modify the strength and efficacy of synaptic transmission through a diverse number of activity-dependent mechanisms.
Long-term potentiation and long-term depression are crucial for synaptic plasticity; defined as the ability to strengthen connections in our synapses and weaken them, respectively. And although this concept seems to be a basic cornerstone in neurology research, like anything in the field of modern neuroscience, it wasn’t that long ago when this process of learning was completely ambiguous. As with all science, the validity of these theories should always be kept in consideration.
1906 Nobel Prize Laureate Santiago Ramón y Cajal was among the first to theorize that learning didn’t involve the formation of new synapses. A few decades later, Canadian psychologist Donald Hebb formed his distinguished Hebb’s postulate, which is often summarized into the phrase “neurons that fire together, wire together,” forming the basis of Hebbian learning in which increased stimulation increases synaptic strength (for machine learning enthusiasts: learn about unsupervised learning/neural networks based on this concept). Long-term potentiation, or LTP, was first observed in the rabbit hippocampus in 1973 by Terje Lømo and Timothy Bliss in the University of Oslo. (They were able to show that a burst of stimulus on perforant path fibres led to a long-lasting change in the postsynaptic response of cells in the dentate gyrus. Their studies also revolutionized the hippocampus as a place of memory storage).
While LTP has been identified in other regions of the brain, it has been extensively studied in the Schaffer collaterals, the axons comprising the synapse between glutaminergic CA3 and CA1 neurons in the hippocampus. Potentiation in this region of the brain involves the NMDA (N-Methyl-d-aspartate) receptor, but it is not the only receptor involved in LTP. For example, in the preceding mossy fibers between the dentate gyrus and the CA3 neurons, the G-protein linked metabotropic glutamate receptors are the primary receptors.
Nonetheless, these receptors bind to glutamate, our brain’s most common excitatory neurotransmitter. (More on neurotransmission will be posted in a future article). Glutamate has several fast excitatory ionotropic receptors: transmembrane proteins permeable to certain ions that simply rely on a first messenger as the trigger to open.
In postsynaptic CA1 neurons, glutamate binds to two of its excitatory ionotropic receptors, NMDA (N-Methyl-d-aspartate) and AMPA ( α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors. NMDA receptors are non-selectively cationic: that is, they are permeable to calcium, and AMPA receptors are selectively cationic, permeable to both to Na+ and K+.
When some outer stimulus is triggered, a neuron is fired, and glutamate is released from the CA3 axon terminal and binds to the NMDA and AMPA receptors. The AMPA receptors open immediately, letting in Na+ and allowing K+ to flow out as they move down their membrane potentials (again, will be explained in a future post). The NMDA receptors open (they also require a glycine along with the glutamate), but ion movement is blocked by a positively charged magnesium ion acting as a voltage sensor.
This is where the aspect of learning comes in. Say you are studying for an upcoming history test and make a flashcard that says the War of 1812 ended in 1815 (if you include the Battle of New Orleans). If you review your flashcard briefly, your neuron will fire once, allowing for the AMPA receptors to open but the Ca2+ influx being inhibited by the Mg2+ ion.
But if you take a second to ponder your flashcard (wasn’t the Treaty of Ghent signed in 1814? Why is it written as 1815?), your neurons will fire multiple times, releasing more and more glutamate, resulting in a greater influx of positive sodium ions via AMPA receptors - enough to repel the Mg2+ in the NMDA receptor via electrostatic forces. Finally, Ca2+, the golden ion when it comes to action potentials, will be allowed into the cell, and trigger a series of enzymatic changes in addition to depolarizing the cell and passing on the signal.
The increase in calcium ions within the postsynaptic cell activates cyclic adenosine monophosphate (cAMP) molecules. This, in turn, activates several kinds of enzymes, some of which increase the number of synaptic receptors, making the synapse more sensitive to neurotransmitters.
The process that was just described is early-phase LTP: when the coincidence receptor NMDA is opened, a rapid influx in Ca2+ leads to cAMP activation, enzymatically activating CaMK (calmodulin-dependent protein kinases), which leads to the exocytosis of more AMPA receptors and phosphorylates pre-existing receptors. Thus, the same amount of glutamate release will lead to more current influx as there are more receptors for it to bind to (less of it gets mopped up by a cleaning crew of astrocytes).
But it gets even better. With repeated stimulation (reviewing your flashcard a few times every week), late-phase LTP is induced. The cellular processes in this phase are not well known, and it is the subject of many neurological studies concerning learning and behavior. Still, it is hypothesized that it involves persistent activation of protein kinases such as MAPK (and more specifically, ERK) which activates CREB (cAMP-response-element-binding). CREB acts in the nucleus of the neuron to epigenetically switch on a series of genes, many of which direct protein synthesis. Other kinases increase dendritic spine formation, postsynaptic density, and activate neurotrophic factors, stimulating the synapse to grow.
This molecular cascade is essential for memories to become long-term. The prevailing view in current neuroscience is that declarative memories are encoded in the hippocampus, then transferred to the frontal lobes for long-term storage and consolidation.
Currently the sea slug Aplysia Californica is the prime model of LTP in research models concerning the gene expression involved in long-term memory and neuroplasticity. As researchers gain new insights into the molecular mechanisms underlying memory, pharmaceutical and technological advances (look into Transcranial Magnetic Stimulation) may enable artificial manipulation of synaptic plasticity.
Long-term potentiation is important in understanding mental illnesses (could harmful memories tied to PTSD be eradicated via long-term depression? (more on this later)), addiction (does the strengthening of certain pathways factor into drug overuse?), and neurodegenerative disorders (does imbalance of dopamine in Parkinson’s and Huntington’s affect synaptic growth?).
And of course, this information is incredibly relevant to help you study for your next test. Every time you are tired of reviewing a flashcard or writing notes, think of all the microscopic processes happening in your synapses: aim for increasing the Ca2+ influx in your learning and watch your memorization skills grow!!
Citations:
Mateos-Aparicio P, Rodriguez-Moreno A. The Impact of Studying Brain Plasticity
Front. Cell. Neurosci., 27 February 2019 doi: 10.3389/fncel.2019.00066
Antonov I, Antonova I, Kandel ER, Hawkins RD. The contribution of activity-dependent synaptic plasticity to classical conditioning in Aplysia. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2001 Aug;21(16):6413-6422. DOI: 10.1523/JNEUROSCI.21-16-06413.2001.
Morris RG, Anderson E, Lynch GS, Baudry M (1986). "Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5". Nature. 319(6056): 774–6. Bibcode:1986Natur.319..774M. doi:10.1038/319774a0. PMID 2869411.
McHugh TJ, Blum KI, Tsien JZ, Tonegawa S, Wilson MA (December 1996). "Impaired hippocampal representation of space in CA1-specific NMDAR1 knockout mice". Cell. 87 (7): 1339–49. doi:10.1016/S0092-8674(00)81828-0. PMID 8980239.
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