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Phenotyping of FGF12AV52H mutation in mouse implies a complex FGF12 network
Jianyu Huang1, Chongyang Sun2, Qian Zhu3
1Shenzhen Key Laboratory of Precision Diagnosis and Treatment of Depression, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Key Laboratory of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China.
Abstract:
Pathogenic missense mutation of the FGF12 gene is responsible for a variable disease phenotypic spectrum. Disease-specific therapies require precise dissection of the relationship between different mutations and phenotypes. The lack of a proper animal model hinders the investigation of related diseases, such as early-onset epileptic encephalopathy. Here, an FGF12AV52H mouse model was generated using CRISPR/Cas9 technology, which altered the A isoform without affecting the B isoform. The FGF12AV52H mice exhibited seizure susceptibility, while no spontaneous seizures were observed. The increased excitability in dorsal hippocampal CA3 neurons was confirmed by patch-clamp recordings. Furthermore, immunostaining showed that the balance of excitatory/inhibitory neurons in the hippocampus of the FGF12AV52H mice was perturbed. The increases in inhibitory SOM+ neurons and excitatory CaMKII+ neurons were heterogeneous. Moreover, the locomotion, anxiety levels, risk assessment behavior, social behavior, and cognition of the FGF12AV52H mice were investigated by elevated plus maze, open field, three-chamber sociability, and novel object tests, respectively. Cognition deficit, impaired risk assessment, and social behavior with normal social indexes were observed, implying complex consequences of V52H FGF12A in mice. Together, these data suggest that the function of FGF12A in neurons can be immediate or long-term and involves modulation of ion channels and the differentiation and maturation of neurons. The FGF12AV52H mouse model increases the understanding of the function of FGF12A, and it is of great importance for revealing the complex network of the FGF12 gene in physiological and pathological processes.
Insights
A new mouse model for FGF12 gene mutations reveals seizure susceptibility and cognitive deficits, aiding research into neurological disorders like epileptic encephalopathy.
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 FGF12AV52H 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 FGF12AV52H 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:
- FGF12AV52H 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 FGF12AV52H 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.
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