PDE4B Missense Variant Increases Susceptibility to Post-traumatic Stress Disorder-Relevant Phenotypes in Mice

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Genome-wide association studies (GWASs) link intronic PDE4B variants to increased risk for post-traumatic stress disorder (PTSD), schizophrenia, and substance use disorders.
• The precise pathophysiological mechanisms underlying the genetic risk associated with PDE4B remain poorly understood.

Purpose of the Study:

• To investigate the functional consequences of PDE4B genetic variation on phenotypes relevant to psychiatric disorders.
• To examine the impact of the rare coding variant M220T (rs775201287) in PDE4B on cellular and behavioral outcomes.

Main Methods:

• HEK-293 cells expressing PDE4B1-M220T were analyzed for cAMP signaling response to forskolin.
• Homozygous Pde4b^M220T mice underwent behavioral testing, including novel environment exploration, acoustic startle, prepulse inhibition, fear conditioning, and spatial memory tasks.
• Neuronal activity, plasma corticosterone levels, and fear memory persistence were assessed in mice following a traumatic event (tone-shock pairings).

Main Results:

• PDE4B1-M220T exhibited an attenuated forskolin-induced cAMP response in HEK-293 cells.
• Pde4b^M220T mice displayed increased reactivity, startle hyperreactivity, prepulse inhibition deficits, altered fear conditioning, and enhanced spatial memory.
• Trauma exposure in Pde4b^M220T mice led to decreased cortical and increased amygdala/hippocampal neuronal activity, reduced corticosterone levels, and persistent fear memory.

Conclusions:

• The PDE4B M220T variant impairs cAMP signaling and confers PTSD-relevant behavioral phenotypes in mice.
• These findings provide a valuable mouse model for studying PDE4B's role in PTSD pathophysiology and highlight its potential as a therapeutic target.