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Patients with Fragile X syndrome, the leading monogenetic cause of autism, suffer from impairments related to the prefrontal cortex, including working memory and attention. Synaptic inputs to the distal dendrites of layer 5 pyramidal neurons in the prefrontal cortex have a weak influence on the somatic membrane potential. To overcome this filtering, distal inputs are transformed into local dendritic Na+ spikes, which propagate to the soma and trigger action potential output. Layer 5 extratelencephalic (ET) prefrontal cortex (PFC) neurons project to the brainstem and various thalamic nuclei and are therefore well positioned to integrate task‐relevant sensory signals and guide motor actions. We used current clamp and outside‐out patch clamp recording to investigate dendritic spike generation in ET neurons from male wild‐type and Fmr1 knockout (FX) mice. The threshold for dendritic spikes was more depolarized in FX neurons compared to wild‐type. Analysis of voltage responses to simulated in vivo 'noisy' current injections showed that a larger dendritic input stimulus was required to elicit dendritic spikes in FX ET dendrites compared to wild‐type. Patch clamp recordings revealed that the dendritic Na+ conductance was significantly smaller in FX ET dendrites. Taken together, our results suggest that the generation of Na+‐dependent dendritic spikes is impaired in ET neurons of the PFC in FX mice. Considering our prior findings that somatic D‐type K+ and dendritic hyperpolarization‐activated cyclic nucleotide‐gated‐channel function is reduced in ET neurons, we suggest that dendritic integration by PFC circuits is fundamentally altered in Fragile X syndrome. Key points: Dendritic spike threshold is depolarized in layer 5 prefrontal cortex neurons in Fmr1 knockout (FX) mice.Simultaneous somatic and dendritic recording with white noise current injections revealed that larger dendritic stimuli were required to elicit dendritic spikes in FX extratelencephalic (ET) neurons.Outside‐out patch clamp recording revealed that dendritic sodium conductance density was lower in FX ET neurons. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)