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Human cortical pyramidal neurons are large, have extensive dendritic trees, and yet have unexpectedly fast input-output properties: Rapid subthreshold synaptic membrane potential changes are reliably encoded in timing of action potentials (APs). Here, we tested whether biophysical properties of voltage-gated sodium (Na+) and potassium (K+) currents in human pyramidal neurons can explain their fast input-output properties. Human Na+ and K+ currents exhibited more depolarized voltage dependence, slower inactivation, and faster recovery from inactivation compared with their mouse counterparts. Computational modeling showed that despite lower Na+ channel densities in human neurons, the biophysical properties of Na+ channels resulted in higher channel availability and contributed to fast AP kinetics stability. Last, human Na+ channel properties also resulted in a larger dynamic range for encoding of subthreshold membrane potential changes. Thus, biophysical adaptations of voltage-gated Na+ and K+ channels enable fast input-output properties of large human pyramidal neurons.

In chapter 2, we recorded AP shapes and underlying Na+ and K+ currents in human cortical pyramidal neurons and compared them to rodents. We found that not only the AP shape, but also the underlying currents have remarkable stability, even when firing hundreds of consecutive APs at frequencies of 60 Hz. We then argued that biophysical adaptations in voltage-gated sodium and potassium channels must be responsible, and tested this by characterizing the voltage-dependent properties of the Na+ and K+ currents. We find that human Na+ and K+ currents had different biophysical features than their mouse counterparts. Then we used in silico models and found that indeed, the observed gating properties result in more stable APs. Furthermore, the models with human-like channel biophysics were able to reliably encode a larger range of inputs than models with rodent-like biophysics. Based on this we concluded that adaptations in the biophysical gating of Na+ and K+ channels contribute to the computational properties of human neurons. Fast Spiking interneurons (FSINs) are specialized in fast input-to-output conversion. The whole neuron is filled with adaptations that support this fast function. Therefore, this is the perfect neuron to study when interested in the speed limits of neural processing. In the human cortex, neurons are spaced further apart to make space for all the elaborate dendritic and axonal trees, which are much more interconnected than in rodents. This could potentially slow down neural signaling, as signals take time to travel and become weaker and slower over distance. Yet neural signaling seems not to be slow in human neurons. In this chapter, we investigated whether and how human FSINs can retain their fast function. We first characterized the dendritic morphology of these neurons and found that indeed, their dendritic paths are much longer. However, when we made paired recordings we did not find a slowdown of input and output, indicating that some compensatory