Jan 28 2022 7 mins 1
Neuroplasticity, or the ability of the brain to change, is a huge term that encompasses all the things that make humans who they are. It is why some deaf people are more sensitive to vibrations and body language. The stroke patient who suffers aphasia sometimes learns to speak again. It is how people learn after repeated exposure to something, and how muscles follow complex patterns, seemingly effortlessly, such as riding a bicycle. Neuroplasticity is how humans can overcome ingrained patterns of behavior and effectively rewire after emotional trauma, often with conscious effort alone. To understand neuroplasticity, one must first understand neurotransmitters, neuronal signaling, signal transduction cascades, and the targets of these cascades. This paper will break this process down into a story: The story of a signal.
In the beginning, there was a signal. The signal was like any other, with characteristic features and a drive to move forward. It did not have parents, per se, but it came from somewhere. Before its existence, the environment to which it was born was negative, -60mV to be exact (Higgins & George, 2019). One might say in this instance, and Stahl (2020) did say it, that the surrounding milieu was just bursting with readiness for the signal. Voltage-gated ion channels sensitive to sodium lined the length of the neuron’s axon, and those sensitive to calcium stood at attention at the axon boutons. Neurotransmitters were packaged tightly in tiny vesicles in axon terminals located at the end of the axon and en passant, as the axon passes by. The synapses, or junctions, lay in wait at the ends of the neuron (Stahl, 2020). Reminiscent of the usual origin questions, the synapse existed long before this signal, and if one went back further, there was another signal before this signal, and another signal before that. Who knows what really started everything? In the case of this synapse, the synapse represented a great change for the signal. The signal worried about when it would have to cross the synaptic cleft, that great chasm in the brain. Would there be a receptor on the receiving neuron to welcome it? Would it have influence in the greater world? Would it be blocked? Would the signal get sidetracked? What is the meaning of life? These are the questions that bothered the signal.
When the time came for the signal to charge into existence, something strange happened. Stahl (2020) described it as starting after a building storm in the post-synaptic terminal overwhelmed the voltage sensitive sodium channels (VSSC). They opened and let in large amounts of positive sodium, which caused the milieu to become less negative. In that instant, the signal began. It traveled along the length of the axon, following in the wake of all the opening VSSCs. At the axon bouton, the voltmeter of the voltage sensitive calcium channels (VSCC) sensed all this positivity, causing them to also open, and leading to an inward flux of calcium. The VSCC thus snared vesicles at the end of the axon and released their contents into the synaptic cleft (Stahl, 2020). This is where the signal went too, because now the signal was the neurotransmitter.
The signal had always expected to be met by the right receptor on the post-synaptic membrane, acting as a perfect agonist that would encourage that receptor to do what it was made to do. It only hoped it would not be an antagonist or reverse agonist, seemingly holding back the receptor by blocking stimulation or even blocking its intrinsic baseline, or constitutive activity (Stahl, 2020). On what came next, a lot of authors had a lot of things to say, and Gordillo-Salas et al. (2020) were no different. They observed that this signal needed a little help from a ligand-gated ion channel (LGIC) and positive allosteric modulators (PAMs). The LGIC was pentameric, which was annoyingly excessive in the view of the signal. The PAMs came out of nowhere. Maybe they were from a drug taken in or some regulatory thing (Gordillo-Salas et al., 2020). The signal did not know. In the end, the PAMs did enhance the signal’s agonist strength and did not crowd the signal too much, as the PAMs did not bind the same receptor site. Together, with the post-synaptic G-protein-linked receptor (GPLR), the signal entered Erickson’s stage of psychosocial development known as generativity versus stagnation (Corey, 2017).
Stahl (2020), who apparently had a lot to say about the signal, reported the signal would go on to guide the next generation of signals through the long process of GPLR binding, with all the resultant effects (despite the GPLR being even more pompous than the LGIC, with a full SEVEN transmembrane proteins). This signal transduction cascade included many conformational changes that led to the formation of the quaternary complex (the signal, or neurotransmitter, receptor, G-protein, and an enzyme). The quaternary complex caused the release of the second messenger, who in turn activated protein kinase A, who phosphorylated CREB, who translocated into the nucleus of the cell and resulted in gene transcription. Gene transcription determined how many receptors to put on neurons and which neuronal connections to strengthen and prune (Stahl, 2020). Gene transcription was all-powerful in the world of neuroplasticity. Karim et al. (2021) liked to say, “use it and improve it or lose it” (p. 301). The adage proved true. Because the signal was not the first signal to use this pathway, but rather one of many, generativity occurred (Karim et al., 2021).
While this story could have happened with any number of signals acting as agonists, antagonists, inverse agonists, or as neuromodulators, one specific path was easier to use to relate the story of this signal. Positive or negative allosteric modulators could have made signal transmission more, or less, likely. Plasticity does not occur with every signal, rather it specifically requires strong or salient signals, many signals occurring temporally, or just many signals, like this signal had. Due to the chain of events in the preceding story, our beloved signal achieved self-actualization. It was a happy ending.
References
Corey, G. (2017). Theory and practice of counseling and psychotherapy (10th ed.). Cengage
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Gordillo-Salas, M., Pascual-Antón, R., Ren, J., Greer, J., & Adell, A. (2020). Antidepressant-like
effects of CX717, a positive allosteric modulator of AMPA receptors. Molecular Neurobiology, 57(8), 3498–3507. https://doi.org/10.1007/s12035-020-01954-x
Higgins, E.S., & George, M.S. (2019). The neuroscience of clinical psychiatry: The
pathophysiology of behavior and mental illness (3rd Ed.). Wolters Kluwer.
Karim, A. K. M. R., Proulx, M. J., de Sousa, A. A., & Likova, L. T. (2021). Neuroplasticity and
crossmodal connectivity in the normal, healthy brain. Psychology & Neuroscience, 14(3), 298–334. https://doi.org/10.1037/pne0000258
Stahl, S.M. (2020). Essential psychopharmacology: Neuroscientific basis and practical
applications (5th ed.). Cambridge University Press.
