Neuron with glowing acidic organelles releasing calcium ions.

Unlocking Memory: How Acidic Brain Cells Hold the Key to Learning

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Elliot Brynn in Science & Nature August 2025 • 4 min read.

"New research reveals the surprising role of acidic calcium stores in neurons, offering potential breakthroughs for treating cognitive disorders."


Our brains are powerhouses of activity, constantly rewiring connections as we learn and remember. At the heart of this process is glutamate, a key neurotransmitter that excites neurons and sets off a cascade of signals. Understanding how glutamate works is crucial for unraveling the mysteries of memory and finding new ways to treat cognitive decline.

Scientists have long known that metabotropic glutamate receptors (mGluRs) play a vital role. These receptors, activated by glutamate, trigger the release of calcium ions (Ca2+) within cells. This calcium release was traditionally thought to originate from a cellular structure called the endoplasmic reticulum (ER). However, recent research is uncovering a more complex picture, highlighting the importance of "acidic Ca2+ stores."

A new study by Foster et al. sheds light on these acidic Ca2+ stores and their unexpected role in long-term potentiation (LTP), a process crucial for strengthening connections between neurons and forming memories. This article will explore their findings and discuss the implications for our understanding of brain function and potential therapeutic interventions.

The Acidic Side of Memory: Unveiling NAADP's Role

Neuron with glowing acidic organelles releasing calcium ions.

Acidic Ca2+ stores are a diverse group of organelles, including lysosomes, that maintain a highly acidic environment and store calcium. These stores communicate with the rest of the cell through the Ca2+-mobilizing messenger nicotinic acid adenine dinucleotide phosphate (NAADP) and two-pore channels (TPCs). Although scientists have observed NAADP's involvement in various neuronal processes, its specific role in learning and memory has remained elusive – until now.

Foster and colleagues' work focuses on how NAADP interacts with mGluR1, a specific type of glutamate receptor, in hippocampal neurons. Their experiments revealed a fascinating chain of events:

  • NAADP Activation: When mGluR1 is stimulated, it triggers the release of NAADP.
  • Acidic Store Release: NAADP then acts on TPCs located on acidic Ca2+ stores, causing them to release calcium.
  • RyR Involvement: This calcium release, in turn, activates ryanodine receptors (RyRs) on the ER, leading to further calcium release.
  • Depolarization: The combined effect of these calcium releases leads to depolarization, a change in the neuron's electrical potential that is essential for LTP.
This intricate interplay between NAADP, acidic Ca2+ stores, and the ER suggests a carefully orchestrated signaling pathway. The researchers found that blocking any of these steps – disrupting acidic organelles or inhibiting RyRs – prevented the depolarization and, consequently, impaired LTP.

Future Directions: Targeting Acidic Calcium Stores for Cognitive Enhancement

The study also highlights the role of small conductance calcium-activated potassium (SK) channels in regulating neuronal excitability. The researchers propose that after calcium release from acidic stores, a phosphatase called PP2A inhibits SK channels, leading to further depolarization. This part is still speculative but a new target of research.

These findings have significant implications for understanding and treating cognitive disorders. Lysosomal dysfunction, which affects acidic Ca2+ stores, is increasingly implicated in neuronal dysfunction and diseases like Alzheimer's. By understanding how NAADP and acidic Ca2+ stores contribute to synaptic plasticity, we may be able to develop targeted therapies to enhance cognitive function and combat neurodegenerative diseases.

The work of Foster et al. opens new avenues for research and provides a compelling case for considering acidic Ca2+ stores as key players in neuronal signaling and synaptic plasticity. As we continue to unravel the complexities of the brain, these discoveries may pave the way for novel treatments that improve the lives of individuals affected by cognitive impairments.

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Everything You Need To Know

1

What is the role of glutamate in learning and memory?

The primary role of glutamate is as a key neurotransmitter that excites neurons, initiating a cascade of signals within the brain. This excitation is crucial for learning and memory because it sets the stage for the rewiring of connections between neurons, a process essential for forming new memories and retaining information. Understanding glutamate's function is vital for comprehending cognitive processes and developing treatments for conditions affecting memory.

2

What are acidic Ca2+ stores, and why are they important?

Acidic Ca2+ stores are specialized organelles, including lysosomes, within neurons that maintain an acidic environment and store calcium ions (Ca2+). Their significance lies in their role in long-term potentiation (LTP), a cellular process that strengthens synaptic connections between neurons, thereby facilitating memory formation. These stores communicate with the rest of the cell through NAADP and TPCs, highlighting their importance in neuronal signaling and the intricate mechanisms underlying learning and memory.

3

How do metabotropic glutamate receptors (mGluRs) contribute to memory?

Metabotropic glutamate receptors (mGluRs) are activated by glutamate and play a crucial role in learning and memory by triggering the release of calcium ions (Ca2+) within neurons. Specifically, the activation of mGluR1, a subtype of mGluRs, initiates a signaling cascade involving NAADP and acidic Ca2+ stores. This cascade leads to the release of Ca2+ and ultimately contributes to the process of long-term potentiation (LTP), which is fundamental for memory formation and synaptic plasticity.

4

What is the role of NAADP in the context of memory formation?

NAADP is a Ca2+-mobilizing messenger that plays a key role in the interaction between mGluR1 and acidic Ca2+ stores. When mGluR1 is stimulated by glutamate, it triggers the release of NAADP, which then acts on TPCs located on acidic Ca2+ stores. This action causes the release of calcium ions, which subsequently activate RyRs on the endoplasmic reticulum (ER), leading to further calcium release. This intricate pathway is crucial for the depolarization of neurons, a process essential for long-term potentiation (LTP) and memory formation.

5

What is long-term potentiation (LTP), and how does it relate to the other concepts?

Long-term potentiation (LTP) is a cellular process vital for strengthening connections between neurons, which is fundamental for forming memories. In the context provided, LTP is directly linked to the interplay between NAADP, acidic Ca2+ stores, and the ER. The release of calcium from acidic stores, facilitated by NAADP and the activation of RyRs, contributes to the depolarization of neurons, which is a critical step in LTP. Impairing any component of this pathway disrupts LTP, thereby affecting memory formation.

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