Prefrontal TRPM8 Receptor Modulates Epileptic Seizures via PKA/CREB Signaling Pathway in Mice

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Epilepsy affects 50 million worldwide, often with cognitive impairments.
• Transient receptor potential melastatin 8 (TRPM8) receptors are implicated in acute seizure models.
• The precise role of prefrontal TRPM8 in seizure mechanisms remains largely unknown.

Purpose of the Study:

• Investigate the upstream and downstream signaling pathways of prefrontal TRPM8 receptors.
• Determine how TRPM8 jointly regulates seizure occurrence and progression.
• Explore TRPM8 as a potential therapeutic target for seizure disorders.

Main Methods:

• Established an acute mouse seizure model using pentylenetetrazol (PTZ).
• Utilized stereotactic injections for region-specific TRPM8 channel blockade in the prefrontal cortex (PFC).
• Analyzed seizure behavior, TRPM8 downstream signaling molecules (p-PKA, p-CREB), and neuronal apoptosis (TUNEL staining) post-PTZ induction.

Main Results:

• TRPM8 receptors and downstream p-PKA/p-CREB levels were upregulated in the PFC during PTZ-induced seizures.
• Inhibiting or knocking down TRPM8 in the PFC prolonged seizure latency and reduced seizure severity.
• TRPM8 inhibition decreased prefrontal neuronal apoptosis, an effect counteracted by PKA activation.

Conclusions:

• Prefrontal TRPM8 receptors are critical in PTZ-induced acute seizures.
• The PKA/CREB pathway is a key downstream mediator of TRPM8's role in seizures.
• Targeting prefrontal TRPM8 offers a promising therapeutic strategy for seizure management.