Genetics of neurodevelopmental syndromes
Gene mutations with high penetration account for only a fraction of language-related pathologies. However, they are essential for understanding the common mechanisms of these disorders. The mutations of forkhead box protein p2 (Foxp2) transcription factor provide the example of a gene specifically implicated in a speech and language disorder. Affected individuals have difficulty mastering the orofacial motor sequences as well as other deficits in oral and written language. Interestingly, the disruption of the closely related Foxp1 gene has been reported in multiple cases of cognitive dysfunction, including intellectual disability and autism spectrum disorder. The EU-funded CORTICAL FOXP2 project investigated the role of Foxp1 and Foxp2 in the development and function of cortical neurons. Researchers employed their newly generated transgenic mouse model with brain-specific Foxp1 deletion. They found that abnormal neuronal morphogenesis of hippocampal CA1 pyramidal cells in transgenic mice correlated with reduced excitability and an imbalance of excitatory to inhibitory input in the neurons. Additionally, Foxp1 ablation was associated with various cognitive and social deficits. Next, researchers investigated the role of Foxp2 in the cortex using mice carrying (R552H) mutation identical to the mutation identified in the case of familial speech and language disorder. The results showed that cortical neurons expressing the mutant form of Foxp2 had altered excitability and decreased potassium channel expression. In addition, the frequency of excitatory postsynaptic currents was decreased. The study demonstrated that Foxp1 and Foxp2 share similar roles in the control of neuronal morphology and neuronal excitability. The amplitude of excitatory postsynaptic currents was increased in Foxp1-deficient neurons, while the frequency (but not the amplitude) of excitatory postsynaptic currents was decreased in the case of Foxp2R552H mutation. In conclusion, the project found that genes involved in language disorders impact the balance of excitatory and inhibitory inputs in the cortex, and control neuronal excitability and dendritic length. This observation creates an important step towards future molecular therapies for the treatment of neurodevelopmental disorders.
