Summary: Researchers have identified a direct interaction between two brain proteins—MAP6 and Kv3.1—that is essential for normal movement, anxiety regulation, and memory in mice. Disrupting this interaction produces hyperactivity, diminished risk avoidance, and memory impairments—features that overlap with some symptoms observed in schizophrenia.
The team reports that MAP6 and Kv3.1 physically bind under normal conditions in several brain regions, and that this binding is crucial for stabilizing Kv3.1 channels in a specific class of fast-spiking interneurons. Understanding this relationship may point to new avenues for therapeutic strategies targeting schizophrenia-related circuit dysfunction.
Key Facts:
- This is the first study to demonstrate that MAP6 and Kv3.1 directly interact in the healthy brain and that their interaction regulates behavior in mice.
- Impairing the interaction between MAP6 and Kv3.1 produced behavioral changes often associated with schizophrenia, including hyperactivity, lower avoidance of risk, and deficits in recognition memory.
- Both MAP6 and Kv3.1 have been identified previously as risk-related proteins in schizophrenia through post-mortem and genetic studies; this work links their molecular relationship to specific neural circuit functions.
Source: Ohio State University
Discovery and significance
Researchers at The Ohio State University report a conserved cytoskeleton–membrane interaction between microtubule-associated protein 6 (MAP6) and the Kv3.1 voltage-gated potassium channel in parvalbumin-positive (PV+) fast-spiking GABAergic interneurons. This interaction stabilizes Kv3.1 channel levels in those interneurons and helps maintain balanced neural signaling important for movement, emotion, and memory.
Using genetically modified mice and targeted molecular interventions, the investigators showed that loss of MAP6 or Kv3.1, or disruption of their binding, alters behaviors that depend on the hippocampus and amygdala. Specifically, inhibiting MAP6–Kv3.1 binding in the amygdala reduced risk avoidance—mice showed less fear of height—while disrupting the interaction in the hippocampus produced hyperactivity and impaired recognition memory for familiar objects.
These behavioral changes mirror several features reported in previous mouse models lacking one or both genes, and they refine those findings by identifying the brain regions where the interaction has the strongest behavioral impact. The results suggest that distinct physiological functions—such as anxiety regulation, locomotor control, and memory—are tied to the interaction between MAP6 and Kv3.1 in specific neural circuits.
Mechanism revealed
Biochemistry and cell biology assays revealed how MAP6 supports Kv3.1: two microtubule-binding modules of MAP6 bind with high affinity to the Kv3.1 tetramerization domain. This binding maintains Kv3.1 channel levels in both neuronal somas and axons. When MAP6 expression falls, Kv3.1 protein levels in PV+ interneurons drop substantially, impairing those interneurons’ ability to generate high-frequency firing and to regulate the balance of excitation and inhibition across affected circuits.
The investigators propose that insufficient Kv3.1 in these interneurons leads to reduced inhibitory control, elevating projection neuron activity in targeted circuits and producing the observed behavioral deficits. Because PV+ fast-spiking interneurons are central to controlling network oscillations and timing, their dysfunction is a compelling therapeutic target for disorders that include cognitive and behavioral disturbances, such as schizophrenia.
Implications for schizophrenia research and treatment
Both MAP6 and Kv3.1 have been implicated in schizophrenia from earlier post-mortem and genetic studies. This study advances that work by providing a molecular link between these two risk-associated proteins and by mapping how disrupting their interaction alters specific brain-region functions and behaviors in mice. Identifying how MAP6 stabilizes Kv3.1 suggests potential strategies to restore channel stability or interneuron function—strategies that could be explored as novel treatment directions for symptoms related to interneuron dysfunction in schizophrenia.
Lead author Chen Gu, associate professor of biological chemistry and pharmacology, emphasizes that while more than 100 genes have been associated with schizophrenia risk, mechanistic links are often missing. This work provides one such link and offers a clear experimental path for testing interventions that target the MAP6–Kv3.1 interaction or its functional consequences in neural circuits.
Study details
The study appears in the journal Molecular Psychiatry. The research combined behavioral analysis of knockout and region-specific knockdown mice with biochemical binding studies and cellular localization experiments to demonstrate both the functional and mechanistic relationship between MAP6 and Kv3.1.
Funding: This research was supported by grants from the National Institutes of Health.
Additional co-authors include Chao Sun, Rahul Manne, Tianqi Guo, Joshua Barry, Thomas Magliery and Houzhi Li of Ohio State and Christophe Bosc and Annie Andrieux of the Grenoble Institut Neurosciences in France.
About this schizophrenia research news
Author: Emily Caldwell
Source: Ohio State University
Contact: Emily Caldwell – Ohio State University
Image credit: Neuroscience News
Original Research: Closed access. “A cytoskeleton-membrane interaction conserved in fast-spiking neurons controls movement, emotion, and memory” by Chen Gu et al., Molecular Psychiatry.
Abstract
A cytoskeleton–membrane interaction conserved in fast-spiking neurons controls movement, emotion, and memory
Schizophrenia’s pathogenesis likely involves combined dysfunctions of many proteins, including MAP6 and the Kv3.1 voltage-gated potassium channel, but their functional relationship has been unclear. This study reports that MAP6 stabilizes Kv3.1 channels in PV+ fast-spiking GABAergic interneurons, and that loss of MAP6 or Kv3.1 produces similar behavioral abnormalities—hyperactivity and reduced avoidance. MAP6 and Kv3.1 colocalize in PV+ interneurons, and MAP6 deletion significantly reduces Kv3.1 protein levels. Two microtubule-binding modules of MAP6 bind the Kv3.1 tetramerization domain with high affinity, maintaining channel levels in soma and axons. Region-specific MAP6 knockdown in the amygdala or hippocampus reduced avoidance or caused hyperactivity and recognition memory deficits, respectively, by elevating projection neuron activity. Knocking down Kv3.1 or disrupting MAP6–Kv3.1 binding in these regions produced comparable behavioral effects. Disrupting this conserved cytoskeleton–membrane interaction in fast-spiking neurons therefore creates circuit-specific vulnerabilities that affect movement, emotion, and memory.