‘Maestro’ protein CASKIN2 orchestrates memory by fine-tuning neuron signals

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For the first time, researchers identified the function of the CASKIN2 protein, which plays a key role in precise signal transmission between neurons and memory formation in the brain. This study is expected to provide important scientific clues for understanding the causes of various brain diseases, such as Alzheimer’s disease and autism spectrum disorder, resulting from synaptic dysfunction, and for developing new treatment strategies.

The work is published in the journal Proceedings of the National Academy of Sciences.

How CASKIN2 influences brain function

The human brain processes information and stores memories through hundreds of billions of neurons that communicate via special connection structures called synapses. In this process, the signal-sending side (presynaptic terminal) and the signal-receiving side (postsynaptic terminal) of the synapse need to be precisely aligned at the nanometer scale to allow accurate signal transmission. However, the molecular mechanisms regulating this alignment remain unclear.

In this study, the team confirmed that the CASKIN2 protein, located at the presynaptic terminal, is a key factor in regulating the function and strength of excitatory synapses, and specifically that the structurally similar CASKIN1 protein does not perform this function, while CASKIN2 has a unique and irreplaceable role in signal transmission.

The core achievement of this study is the discovery that CASKIN2 functions in signal-sending neurons and directly influences the activity of signal-receiving neurons. In other words, CASKIN2 acts as a “maestro,” coordinating all communication between two cells across the space between synapses. The research team confirmed that this occurs through interaction with another protein called PTPσ.

When PTPσ dephosphorylates (the process of chemically switching it on) a specific region of CASKIN2, it rearranges the cytoskeletal structure of the presynaptic terminal, enabling stable signal transmission. Consequently, it enhances the function of the signal receptor (NMDA receptor) at the postsynaptic terminal receiving the signal, facilitating the transmission of information between neurons.

Experimental evidence and implications

The research team showed that these protein interactions directly affect actual learning and memory formation in mouse experiments. Mice with the functions of CASKIN2 or PTPσ in the hippocampal neural circuit, the brain’s memory center, removed, exhibited a clear decline in spatial memory, the ability to recall new locations. This result clearly demonstrates that protein function at the molecular level is the foundation of learning and memory, which are higher cognitive functions.

Professor Ko Jae-won stated, “Through this study, we have clarified at the molecular level how CASKIN2 in signal-transmitting cells interacts with the PTPσ protein to regulate the function of signal-receiving cells and how this action contributes to the memory formation process. This provides important clues to how precise communication between neurons occurs, and will serve as a scientific foundation for the development of new brain disease treatments targeting the CASKIN2-PTPσ protein.”

This research was carried out by researcher Jang Gyu-bin from the Center for Synapse Diversity and Specificity at DGIST’s Department of Brain Science, serving as a co-lead author. Additionally, Professor Han Kyung-ah from Chungnam National University College of Medicine was listed as a co-lead author and co-corresponding author.

The molecular mechanism behind CASKIN2

This molecular model explains how the interaction between the presynaptic adhesion protein PTPσ and CASKIN2 regulates the function of postsynaptic NMDA receptors and synaptic properties. Specifically, CASKIN2 acts as a central axis that coordinates actin polymerization at presynaptic terminals, depending on neural activity.

At this stage, dephosphorylation of CASKIN2 by PTPσ and its subsequent multimerization are essential mechanisms as these processes ultimately determine the cell surface expression of NMDA receptors, excitatory neurotransmission, synaptic strength, and plasticity.