Phenotyping of FGF12A^V52H mutation in mouse implies a complex FGF12 network

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Pathogenic mutations in the FGF12 gene cause a range of diseases.
• Understanding genotype-phenotype correlations is crucial for developing targeted therapies.
• A lack of suitable animal models impedes research into FGF12-related disorders, including early-onset epileptic encephalopathy.

Purpose of the Study:

• To generate and characterize a novel mouse model for studying FGF12 gene mutations.
• To investigate the impact of the FGF12A^V52H mutation on neuronal function and behavior.
• To explore the role of FGF12A in neuronal excitability, differentiation, and maturation.

Main Methods:

• CRISPR/Cas9 technology was used to create the FGF12A^V52H mouse model, specifically targeting the A isoform.
• Electrophysiological recordings (patch-clamp) were performed on dorsal hippocampal CA3 neurons.
• Immunostaining was used to analyze the balance of excitatory and inhibitory neurons.
• Behavioral tests including elevated plus maze, open field, three-chamber sociability, and novel object recognition were conducted.

Main Results:

• FGF12A^V52H mice displayed increased seizure susceptibility but no spontaneous seizures.
• Patch-clamp recordings confirmed enhanced excitability in dorsal hippocampal CA3 neurons.
• Hippocampal immunostaining revealed perturbed excitatory/inhibitory neuron balance, with heterogeneous increases in SOM+ and CaMKII+ neurons.
• Behavioral analyses indicated cognitive deficits, impaired risk assessment, and altered social behavior, despite normal social indexes.

Conclusions:

• The FGF12A^V52H mouse model provides valuable insights into the function of FGF12A in neuronal processes.
• FGF12A appears to modulate ion channels and influence neuronal differentiation and maturation, with both immediate and long-term effects.
• This model is crucial for advancing the understanding of FGF12 gene networks in health and disease, particularly for epileptic encephalopathy.