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Neurons and learning: activity-driven neuroplasticity

Shriya Singh

When we start learning a new skill, every little aspect requires deliberate, conscious effort. With practice and repetition, our actions become smoother and easier to recall, eventually transforming initially demanding skills into second nature. Underlying this process of skill acquisition are intricate firing patterns in brain networks, a phenomenon known as long-term potentiation (LTP), or "activity-driven neuroplasticity." LTP strengthens specific synaptic connections without affecting others, maintaining input specificity. Its counterpart, long-term depression (LTD), works in the opposite direction. Together, LTP and LTD play crucial roles in fine-tuning neural circuits, which are essential for learning and memory, and rely on similar neurological processes at the molecular level.


Molecular mechanisms


The concept of LTP was introduced over 30 years ago, but its underlying molecular mechanisms remained elusive until the 1980s, when key insights identified NMDA (N-methyl-D-aspartate) receptors as central players. These Ca²⁺ channels in the brain are unique because they are blocked by Mg²⁺ ions at resting membrane potentials. During low-frequency stimulation, smaller action potentials activate AMPA receptors by facilitating glutamate binding, but NMDA receptors remain blocked by Mg²⁺. Only when the neuronal membrane depolarizes sufficiently to expel the Mg²⁺ ion do NMDA receptors open, allowing Ca²⁺ to enter the postsynaptic neuron.


Importantly, the unique properties of NMDA receptors explain LTP's specificity and associativity. When one group of synaptic inputs is strongly activated, LTP occurs only at those specific synapses, as NMDA receptors at other synapses fail to meet the activation threshold. For associativity, weakly stimulated synapses alone cannot depolarize the neuron enough to remove the Mg²⁺ block. However, if neighboring synapses are strongly activated, they can provide sufficient depolarization, enhancing Ca²⁺ influx through NMDA receptors at the weakly stimulated synapse and inducing LTP.


"LTP is closely linked to learning processes in the hippocampus, the brain region critical for memory formation."

Ca²⁺ influx is critical for LTP, as it activates key protein kinases like CaMKII (calcium/calmodulin-dependent protein kinase II) and Protein Kinase C (PKC). CaMKII, in particular, is abundant in LTP-associated synapses and is thought to increase postsynaptic sensitivity to glutamate by either adding more receptors to the synapse or enhancing the sensitivity of existing ones. Some theories also suggest that LTP involves increased neurotransmitter release from presynaptic neurons through retrograde signaling, where the postsynaptic neuron regulates presynaptic activity using molecules like nitric oxide to strengthen communication.


LTP & learning


LTP is closely linked to learning processes in the hippocampus, the brain region critical for memory formation. Dendritic spines, small protrusions on neurons housing excitatory synapses, are indicators of synaptic growth and restructuring driven by LTP and LTD. These processes are initiated by cascades of Ca²⁺ signaling influenced by pre- and postsynaptic activity. Moreover, LTP occurs in two distinct phases: early-phase LTP, which is transient and prone to decay, and late-phase LTP, which is longer-lasting. Late-phase LTP involves a mechanism called synaptic-tagging-and-capture (STC), where synapses marked during the early phase "capture" proteins necessary for long-term changes. This process helps consolidate and stabilize memories. Interestingly, recent research highlights that LTP decay, an active process occurring within 1-6 hours after induction, is mediated by the endocytosis of AMPA receptors.


"(...) if neighboring synapses are strongly activated, they can provide sufficient depolarization, (...) inducing LTP"

LTP & neurodegenerative conditions


LTP's role also extends to understanding neurodegenerative conditions like Alzheimer’s disease, where impaired synaptic plasticity contributes to cognitive decline. Protein kinase M zeta (PKMζ), essential for maintaining non-decaying LTP, is often mislocalized or degraded due to neurofibrillary tangles. This disruption weakens synaptic strength and memory retention. However, recent advances show promise: the synthetic peptide GluA23Y inhibits AMPA receptor endocytosis, converting decaying LTP into non-decaying LTP and slowing memory loss. Furthermore, GluA23Y has demonstrated the potential to reduce toxic plaques in Alzheimer’s mouse models, making it a promising therapeutic avenue.


In conclusion, long-term potentiation lies at the core of our understanding of how the brain learns and remembers. Through the contributions of NMDA receptors, Ca²⁺ influx, and protein kinases, LTP and LTD shape synaptic plasticity. Its links to neurodegenerative diseases like Alzheimer’s underscore its importance, while innovative interventions like GluA23Y highlight the potential to restore cognitive functions. Exploring the mechanisms of LTP continues to unlock profound insights into brain function and paves the way for transformative therapies in neurodegenerative and cognitive disorders.


 

This article was written by Shriya Singh and edited by Julia Dabrowska, with graphics produced by Lilly Green. If you enjoyed this article, be the first to be notified about new posts by signing up to become a WiNUK member (top right of this page)! Interested in writing for WiNUK yourself? Contact us through the blog page and the editors will be in touch.


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