Increased transient Na⁺ conductance and action potential output in layer 2/3 prefrontal cortex neurons of the fmr1^−/y mouse

Key points: Layer 2/3 neurons of the prefrontal cortex display higher gain of somatic excitability, responding with a higher number of action potentials for a given stimulus, in fmr1^−/y mice. In fmr1^−/y L2/3 neurons, action potentials are taller, faster and narrower. Outside-out patch clamp recordings revealed that the maximum Na⁺ conductance density is higher in fmr1^−/y L2/3 neurons. Measurements of three biophysically distinct K⁺ currents revealed a depolarizing shift in the activation of a rapidly inactivating (A-type) K⁺ conductance. Realistic neuronal simulations of the biophysical observations recapitulated the elevated action potential and repetitive firing phenotype. Abstract: Fragile X syndrome is the most common form of inherited mental impairment and autism. The prefrontal cortex is responsible for higher order cognitive processing, and prefrontal dysfunction is believed to underlie many of the cognitive and behavioural phenotypes associated with fragile X syndrome. We recently demonstrated that somatic and dendritic excitability of layer (L) 5 pyramidal neurons in the prefrontal cortex of the fmr1^−/y mouse is significantly altered due to changes in several voltage-gated ion channels. In addition to L5 pyramidal neurons, L2/3 pyramidal neurons play an important role in prefrontal circuitry, integrating inputs from both lower brain regions and the contralateral cortex. Using whole-cell current clamp recording, we found that L2/3 pyramidal neurons in prefrontal cortex of fmr1^−/y mouse fired more action potentials for a given stimulus compared with wild-type neurons. In addition, action potentials in fmr1^−/y neurons were significantly larger, faster and narrower. Voltage clamp of outside-out patches from L2/3 neurons revealed that the transient Na⁺ current was significantly larger in fmr1^−/y neurons. Furthermore, the activation curve of somatic A-type K⁺ current was depolarized. Realistic conductance-based simulations revealed that these biophysical changes in Na⁺ and K⁺ channel function could reliably reproduce the observed increase in action potential firing and altered action potential waveform. These results, in conjunction with our prior findings on L5 neurons, suggest that principal neurons in the circuitry of the medial prefrontal cortex are altered in distinct ways in the fmr1^−/y mouse and may contribute to dysfunctional prefrontal cortex processing in fragile X syndrome.