TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven...

Area of Science:

• Neuroscience
• Molecular Biology
• Developmental Biology

Background:

• Transient Receptor Potential Canonical 4 (TRPC4) channels are linked to neurological functions and autism.
• The role of TRPC4 in neurodevelopment is not well understood.

Purpose of the Study:

• To investigate the role of TRPC4 in neurodevelopment and behavior.
• To elucidate the molecular mechanisms underlying TRPC4's function in neuronal development.

Main Methods:

• Utilized TRPC4 knockout (Trpc4-/-) mice to assess neurobehavioral deficits.
• Examined dendritic arborization in hippocampal neurons in vivo and in vitro.
• Performed live-cell imaging to study glutamate-induced dendritic branching.
• Investigated TRPC4's role in calcium (Ca2+) signaling downstream of metabotropic glutamate receptors.

Main Results:

• Trpc4-/- mice exhibited early-onset neurobehavioral deficits post-weaning, affecting nesting, burrowing, and social interactions.
• Hippocampal neurons from Trpc4-/- mice showed reduced dendritic branching.
• TRPC4 mediates Ca2+ entry, influencing nonmuscle myosin light chain (MLC) phosphorylation via myosin light chain kinase (MLCK), crucial for integrin activation and dendrite stability.
• Glutamate stimulation led to new branch formation but subsequent retraction in Trpc4-/- neurons.

Conclusions:

• TRPC4 channels are essential for dendrite morphogenesis and motivated behaviors.
• Impaired TRPC4 function leads to deficits in dendritic development and abnormal behaviors in juvenile mice.
• Findings offer insights into neurodevelopmental disorders like autism spectrum disorder and suggest potential therapeutic targets.