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The Fascinating Role of CA2 in the Hippocampus

CA2 is key for memory and social behavior in the brain.

Georgia M. Alexander, Bo He, Austin Leikvoll, Stephanie Jones, Rob Wine, Prakash Kara, Negin Martin, Serena M. Dudek

― 5 min read


CA2: A Key Player in CA2: A Key Player in Memory delivery processes. CA2 impacts social memory and gene
Table of Contents

The hippocampus is a region in our brains that helps with memory and navigation. Within the hippocampus, there are different areas, or "subfields," just like rooms in a house. One of these rooms is called CA2, and it's a bit different from the others. Researchers have found that CA2 has special features that make it fascinating and worth studying.

What Makes CA2 Unique?

Special Genes and Connections

CA2 has a unique set of genes that it uses. These genes help CA2 neurons connect and communicate differently than neurons in other parts of the hippocampus. This area can also change its connections in response to experiences, which is crucial for memory and learning.

Love for Social Interactions

CA2 plays a role in social memory. It's involved in how we remember and respond to social situations. For instance, if you get into a disagreement with a friend, it’s CA2 that helps you recall past interactions to navigate the current social landscape.

Fight or Flight

Besides social memory, CA2 is also linked to defensive behaviors. It influences how we react to threats-like when you see a bear on a hiking trail and your brain goes into high alert mode.

The Curious Case of AAVs and CA2 Neurons

What Are AAVs?

AAVs, or adeno-associated viruses, are tools used by scientists to introduce new genes into cells. Think of them as little delivery trucks that carry important packages to specific addresses in the brain. Scientists want to use AAVs to study how different genes affect brain function.

CA2 Neurons and AAVs

Interestingly, CA2 neurons seem to have a special fondness for AAVs. When researchers inject AAVs, they often find that CA2 is a hot spot for Gene Expression, even when the AAVs are not injected directly into the CA2 area. This has led to some head-scratching questions: Why do these neurons like AAVs so much?

The Role of the Extracellular Matrix

Meet the Perineuronal Nets

Surrounding CA2 neurons are special structures called perineuronal nets, or PNNs for short. Think of them as cozy nets that protect the neurons while also keeping the space around them clean. These nets might help AAVs stick around longer, making sure CA2 neurons have ample time to grab the goodies being delivered.

PNNs: The Good, The Bad, and the Ugly

But here’s the twist: When researchers knocked out PNNs in their experiments, they still found that CA2 neurons could express AAV-delivered genes just fine. So, while the PNNs are nice to have, they’re not the main reason CA2 loves AAVs. It appears CA2 has other tricks up its sleeve!

The Importance of Receptors

How Do AAVs Get Inside?

For AAVs to deliver their precious cargo, they need to get into the cells. They do this by attaching themselves to cell surface receptors-like colorful stickers on a wall. Some receptors in CA2 are particularly good at grabbing AAVs.

AAV Receptor (AAVR): The VIP

At the top of the list is the AAV receptor, commonly called AAVR. It's like the VIP doorbell for AAVs. Without AAVR, the AAVs have a hard time getting in. When researchers tried deleting this receptor, they observed nearly no gene expression. So, AAVR is crucial for AAV transduction.

The Role of Other Glycan Receptors

In addition to AAVR, CA2 neurons are full of other proteins and molecules that help with AAV entrance. These include glycan receptors, which are like little traffic signs directing AAVs to their destination. Scientists found that these receptors are especially abundant in CA2, leading to a higher rate of AAV transduction compared to other areas.

AAVs and Their Favorite Variants

Different AAV Types

Not all AAVs are created equal. Different serotypes (or varieties) of AAVs behave differently. Some AAVs prefer to target certain brain areas over others. In their experiments, researchers discovered that several serotypes favor CA2, while others seem to skip it entirely.

AAV6: The Wild Card

AAV6 is an interesting case. While it doesn’t target CA2 specifically, it can still get inside. Even in animals lacking some of the typical binding factors, AAV6 showed the ability to successfully deliver genes. This means researchers can use AAV6 whenever they want robust expression without the risk of messing with the surrounding areas.

The Power of CAP-B10 AAV

Enter CAP-B10

CAP-B10 is a newer variant of AAV designed for enhanced targeting of specific neurons. Researchers noticed that when they injected CAP-B10 into the bloodstream, it had a great affinity for CA2. This means it can deliver genetic material precisely and effectively, making it a valuable tool for studying the CA2 region without the need for invasive procedures.

Conclusion: AAVs and the Future of Neuroscience

In summary, CA2 is a remarkable part of the brain with a special skill set. It shows unique gene expression and has a significant role in social interactions and defensive behaviors. The way it interacts with AAVs opens new doors in neuroscience research.

As researchers continue to uncover the mysteries of CA2, they’re gearing up to use AAVs as tools to learn more about how this brain region operates. Who knows what fascinating discoveries are waiting in the wings? Perhaps one day, we might figure out how to harness these findings for therapeutic uses or enhance our understanding of complex brain functions.

After all, the brain is a wild place, and CA2 is one of its quirkiest characters!

Original Source

Title: Hippocampal CA2 neurons disproportionately express AAV-delivered genetic cargo

Abstract: Hippocampal area CA2 is unique in many ways, largely based on the complement of genes expressed there. We and others have observed that CA2 neurons exhibit a uniquely robust tropism for adeno-associated viruses (AAVs) of multiple serotypes and variants. In this study, we aimed to systematically investigate the propensity for AAV tropism toward CA2 across a wide range of AAV serotypes and variants, injected either intrahippocampally or systemically, including AAV1, 2, 5, 6, 8, 9, DJ, PHP.B, PHP.eB, and CAP-B10. We found that most serotypes and variants produced disproportionally high expression of AAV-delivered genetic material in hippocampal area CA2, although two serotypes (AAV6 and DJ) did not. In an effort to understand the mechanism(s) behind this observation, we considered perineuronal nets (PNNs) that ensheathe CA2 pyramidal cells and, among other functions, buffer diffusion of ions and molecules. We hypothesized that PNNs might attract AAV particles and maintain them in close proximity to CA2 neurons, thereby increasing exposure to AAV particles. However, genetic deletion of PNNs from CA2 had no effect on AAV transduction. Next, we next considered the AAV binding factors and receptors known to contribute to AAV transduction. We found that the AAV receptor (AAVR), which is critical to transduction, is abundantly expressed in CA2, and knockout of AAVR nearly abolished expression of AAV-delivered material by all serotypes tested. Additionally, we found CA2 enrichment of several cell-surface glycan receptors that AAV particles attach to before interacting with AAVR, including heparan sulfate proteoglycans, N-linked sialic acid and N-linked galactose. Indeed, CA2 showed the highest expression of AAVR and the investigated glycan receptors within the hippocampus. We conclude that CA2 neurons are endowed with multiple factors that make it highly susceptible to AAV transduction, particularly to the systemically available PHP variants, including CAP-B10. Given the curved structure of hippocampus and the relatively small size of CA2, systemic delivery of engineered PHP or CAP variants could all but eliminate the need for intrahippocampal AAV injections, particularly when injecting recombinase-dependent AAVs into animals that express recombinases in CA2.

Authors: Georgia M. Alexander, Bo He, Austin Leikvoll, Stephanie Jones, Rob Wine, Prakash Kara, Negin Martin, Serena M. Dudek

Last Update: 2024-11-28 00:00:00

Language: English

Source URL: https://www.biorxiv.org/content/10.1101/2024.11.27.625768

Source PDF: https://www.biorxiv.org/content/10.1101/2024.11.27.625768.full.pdf

Licence: https://creativecommons.org/publicdomain/zero/1.0/

Changes: This summary was created with assistance from AI and may have inaccuracies. For accurate information, please refer to the original source documents linked here.

Thank you to biorxiv for use of its open access interoperability.

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