Long Term Depression and Its Mechanisms

One of the most quickly growing areas in neuroscience research is the exploration of the mechanisms of plasticity within the nervous system. The idea of neuronal plasticity provides a mechanical explanation for learning and memory within the brain, as well as some other situations, such as sensory adjustment after lost extremities or senses. The most widely studied form of plasticity is long-term potentiation (LTP), which occurs when a neuron has experienced repeated stimulation and as a result, experiences an increase in synaptic strength. One function of LTD is the necessity of action potentials, as there must be a large depolarization in the postsynaptic neuron, allowing the NMDA glutamate receptors to open. While LTP is important and understanding its mechanisms has helped us understand the fluctuations in synapses, long-term depression (LTD) is an area that has not received the attention it deserves. While some may think that LTD is mainly important for undoing the effects of LTP, this is simply not the case. LTD has been observed to be a critical mechanism of synaptic plasticity in itself, having effects that can modulate learning and memory in the brain very similarly to LTP. Researchers have since been attempting to understand the mechanisms of LTD, its effects, and its interactions with LTP.

An article, titled “The times they are a-changin’: a proposal on how brain flexibility goes beyond the obvious to include the concepts of ‘upward’ and ‘downward’ to neuroplasticity” by Cassiano Ricardo Alves Faria Diniz et al., published in Molecular Psychiatry, describes the importance of LTD and how it is often overlooked. The article first describes the well-understood nature of LTP and how it is important for learning and recognition of our environment. Then the article branches from LTP to LTD, stating that neuroplasticity is often considered a purely positive force, however, this is a view that does not encompass the full scope of neuroplasticity. LTD, or “downward neuroplasticity” as the author calls it, is frequently a result of chronic stress or repeated trauma. This is caused by the repetitive low-frequency stimulation that affects specific neurons, triggering LTD. It can also be important in downregulating certain areas of the brain after injury and may be the cause of a large portion of the loss of function we experience as we grow old. Of course, there is always a clinical application, and LTD is no different. LTD can be elicited by certain neurological disorders, such as anxiety, depression, or PTSD, and can exacerbate the effects of the disorders. The author also concludes that we must research LTD further in order to understand the complete scope of neuroplasticity. 

Luckily, there have been recent developments in this field. One article, titled “Pin1 Binding to Phosphorylated PSD-95 Regulates the Number of Functional Excitatory Synapses” by Jary Delgado et al., published in Frontiers In Molecular Neuroscience, describes some of the mechanisms of LTD. The researchers found that postsynaptic density protein 95 (PSD95) is one of the main contributors to synaptic plasticity, and its modifications have implications for LTD. When a neuron experiences LTD, PSD95 is phosphorylated, which allows a protein, Pin1, to bind to it. This binding inhibits the normal palmitoylation of PSD95 that occurs. This is important when you consider the palmitoylation is important for PSD95 to remain expressed at the synapse. With PSD95 being less expressed, there is a decrease in the stability of the synaptic receptors, specifically the glutamate receptors AMPA and NMDA. Over time, the lack of palmitoylation of PSD95 also corresponds with an increase in ubiquitination, which likely corresponds with endocytosis of the glutamate receptors and a marked decrease in synaptic strength and stability over time.

Like many fields of neuroscience, there is still much we do not understand about LTD, its effects, and its mechanisms. Luckily, researchers such as Jary Delgado has been looking at the mechanisms that underlie LTD. With research like this, we may be able to understand neurological disorders better in the future, such as Alzheimer’s Disease.

Works Cited:

Diniz, C. R. A. F., & Crestani, A. P. (2023). The times they are a-changin’: a proposal on how brain flexibility goes beyond the obvious to include the concepts of “upward” and “downward” to neuroplasticity. Molecular Psychiatry, 28(3), 977-992.

Delgado, J. Y., Nall, D., & Selvin, P. R. (2020). Pin1 binding to phosphorylated PSD-95 regulates the number of functional excitatory synapses. Frontiers in molecular neuroscience, 13, 10.