The Potential Role of Two Proteins in Revolutionizing Schizophrenia Therapy

Recent research has uncovered that the interaction between two neural proteins, MAP6 and Kv3.1, plays a crucial role in the regulation of memory, movement, and anxiety behaviors in murine models. These findings may hold the key to developing novel therapeutic approaches for schizophrenia. The absence of interaction between these proteins is associated with adverse behavioral manifestations, indicating their crucial role in the brain regions governing such behaviors. The study points to the possibility of targeting these protein interactions as a means of treating schizophrenia.

A murine study highlights essential elements that influence movement and memory.

A significant breakthrough by scientists reveals a direct physical interaction between two neural proteins, which has been demonstrated in mice to influence movement, anxiety, and memory regulation. This development opens the door to cutting-edge treatment options for schizophrenia, researchers suggest.

The investigative team is pioneering the understanding that these proteins, among the numerous proteins connected to schizophrenia susceptibility, interact normally in various brain areas, a critical factor for maintaining standard movement, memory function, and anxiety control in mice.

The researchers observed that a malfunction in this interaction leads to a deterioration in behavior – evidenced in mice by an increase in hyperactivity, diminished avoidance of danger, and compromised memory. While delusions and hallucinations are the primary symptoms of schizophrenia, the disorder also includes other symptoms such as difficulties with movement and memory.

“The connection between these two seemingly unrelated proteins and the effect of their interaction was previously unknown,” stated Chen Gu, the lead author and associate professor of biological chemistry and pharmacology at The Ohio State University College of Medicine.

“Over 100 genes have been identified as risk factors for schizophrenia, yet the actual mechanisms behind these risks remain unclear,” Gu remarked. “It is our hope that a deeper understanding of this mechanism could eventually contribute to the development of new treatments that could positively affect patients with schizophrenia.”

The research has been recently published in the journal Molecular Psychiatry.

Exploring Protein Interactions and Functions

Prior post-mortem studies that have flagged schizophrenia risk genes were based on observed protein malfunctions in brain tissue samples. This includes MAP6, known for its role in neuron structure, specifically microtubules, and Kv3.1, which regulates neurons’ electrical signaling frequency.

Gu’s laboratory, which has long been examining Kv3.1, particularly in mice genetically modified to lack this gene, has initiated the exploration of the connection between Kv3.1 and MAP6. Di Ma, a graduate student in the laboratory, discovered that mice deficient in both protein genes displayed similar behavioral alterations.

“This prompted us to investigate their interrelationship more closely,” said Gu.

In their latest study, Ma and colleagues delved into how the interaction between these proteins affects behavior by disrupting their binding in specific mouse brain regions: the hippocampus, related to learning and memory, and the amygdala, where emotional processing occurs.

The team discovered that interference with the protein interaction in the amygdala led to decreased avoidance of risks – evidenced in the mice’s lack of fear of heights. Blocking their binding in the hippocampus caused increased activity levels and diminished recognition of familiar objects. While these behavioral changes vary from those seen in mice lacking one or both genes entirely, these results offer significant insights into which brain regions the proteins’ interactions most affect behavior.

“Daily physiological functions are managed by distinct brain regions,” Gu explained. “Our study marks a progression in understanding because, until now, we only knew that mice with global gene knockouts exhibited these behavioral changes, but we didn’t know which specific brain region was responsible.”

Further Research and Implications

Gu’s laboratory is set to investigate potential associations between social behaviors in mice and the functioning of these proteins in the prefrontal cortex, crucial for decision-making and planning.

In a succession of biochemistry and cell biology experiments, the researchers also determined the mechanics of how these proteins bind and how this interaction influences their distribution within neurons. The findings indicate that MAP6 maintains the positioning of the Kv3.1 channel in a particular neuron type, contributing to the regulation of brain signal consistency. Conversely, a reduced expression of MAP6 significantly lowers Kv3.1 levels in those neurons.

These combined discoveries suggest that improper binding of these proteins could result in insufficient Kv3.1 for the maintenance of interneurons’ signal regulation, leading to a neural imbalance between inhibition and excitation in the affected brain areas – and consequently, adverse behavioral symptoms. These interneurons, capable of high-frequency nerve impulse generation, are seen as a strategic focal point for schizophrenia treatment.

“Our study not only establishes a connection between MAP6 dysfunction and interneuron signal imbalance but also reveals a protein interaction that affects one another, unveiling potential new pathways for therapeutic strategies,” Gu stated.

Citation: Di Ma et al., “A cytoskeleton-membrane interaction conserved in fast-spiking neurons controls movement, emotion, and memory,” Molecular Psychiatry, October 13, 2023.
DOI: 10.1038/s41380-023-02286-7

This research received funding from the National Institutes of Health.

The study also involved Chao Sun, Rahul Manne, Tianqi Guo, Joshua Barry, Thomas Magliery, and Houzhi Li from Ohio State, along with Christophe Bosc and Annie Andrieux from the Grenoble Institut Neurosciences in France.

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• Schizophrenia and the Brain
• Protein Interactions in Neuroscience
• Molecular Psychiatry Journal
• National Institutes of Health Research Grants
• Ohio State University College of Medicine
• Grenoble Institut Neurosciences