Haploinsufficiency of Cyfip2 Causes Lithium-Responsive Prefrontal Dysfunction.

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Genetic variants of cytoplasmic FMR1-interacting protein 2 (CYFIP2) are linked to brain disorders like intellectual disability and epilepsy.
• Specific in vivo neuronal defects and treatments for CYFIP2-associated disorders are not well understood.

Purpose of the Study:

• To investigate the neurobehavioral phenotypes and underlying pathological mechanisms in Cyfip2 heterozygous (Cyfip2^+/-) mice.
• To explore potential treatments for CYFIP2-associated phenotypes and identify the neuronal functions involved.

Main Methods:

• Behavioral analyses were conducted on Cyfip2^+/- mice.
• Molecular, ultrastructural, and electrophysiological analyses were performed on prefrontal neurons.
• CYFIP2 was selectively reduced in the prefrontal cortex (PFC) of mice using viral vectors.

Main Results:

• Adult Cyfip2^+/- mice displayed lithium-responsive abnormal behaviors, increased filamentous actin, enlarged dendritic spines, and enhanced excitatory synaptic transmission in layer 5 (L5) prefrontal cortex neurons.
• These mice showed increased seizure susceptibility and altered auditory steady-state responses.
• Lithium selectively normalized L5 neuron hyperexcitability, and reduced CYFIP2 expression induced L5 hyperexcitability and abnormal behaviors.

Conclusions:

• Layer 5-specific prefrontal dysfunction, particularly hyperexcitability, is central to the pathophysiology of CYFIP2-associated brain disorders.
• Lithium treatment effectively ameliorates neurobehavioral phenotypes by targeting this L5-specific hyperexcitability.
• These findings provide insights into CYFIP2-associated brain disorders and potential therapeutic strategies.