Human voltage-gated Na+ and K+ channel properties underlie sustained fast AP signaling

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

Fast and complex neural computation at the basis of cognition

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 mechanism must be at play. This could not be explained by sodium channel gating, as we find similar sodium current properties in human and mouse FSINs. Using biophysical modeling we find that a combination of enlarged synaptic inputs, reduced dendritic complexity and fast outputs in human FSINs are responsible for conserving a fast signaling speed even over large distances. In this chapter, we take the concept of cellular properties as important determinant for computational power of neurons and see how that relates to the function of the brain as a whole. Although we know that genetics and thickness of the cortex play an important role in IQ differences between individual humans, we do not know it’s structural and functional basis. In this first-of-its-kind study, we obtained IQ scores as well as cellular measurements from individuals. We find that high IQ score does not only go together with large cortical thickness of the temporal cortex, but also with increased dendritic complexity and fast AP shapes. This provided the first evidence that human intelligence is related to complexity and speed of information exchange between individual neurons. Strikingly, the increase in cortical thickness with IQ was found to be purely specific to layers 2 and 3 of the cortex. Apparently, these cortical layers, which serve as important computational layers between input and output layers, are pivotal for intelligence. We then confirmed that high IQ relates to lower cell density, larger cells, more complex dendrites and faster AP signaling all specifically to the pyramidal neurons in layers 2 and 3. Furthermore, we find that verbal intelligence correlates with all these microstructural and cellular features, but only on left, not right, temporal cortex

Structural and functional specializations of human fast spiking neurons support fast cortical signaling

Fast spiking interneurons (FSINs) provide fast inhibition that synchronizes neuronal activity and is critical for cognitive function. Fast synchronization frequencies are evolutionary conserved in the expanded human neocortex, despite larger neuron-to-neuron distances that challenge fast input-output transfer functions of FSINs. Here, we test in human neurons from neurosurgery tissue which mechanistic specializations of human FSINs explain their fast-signaling properties in human cortex. With morphological reconstructions, multi-patch recordings, and biophysical modeling we find that despite three-fold longer dendritic path, human FSINs maintain fast inhibition between connected pyramidal neurons through several mechanisms: stronger synapse strength of excitatory inputs, larger dendrite diameter with reduced complexity, faster AP initiation, and faster and larger inhibitory output, while Na+ current activation/inactivation properties are similar. These adaptations underlie short input-output delays in fast inhibition of human pyramidal neurons through FSINs, explaining how cortical synchronization frequencies are conserved despite expanded and sparse network topology of human cortex

Data for "Human voltage-gated Na+ and K+ channel properties underlie sustained fast AP signaling" article

These data files accompany article "Human voltage-gated Na+ and K+ channel properties underlie sustained fast AP signaling" by René Wilbers and colleagues, 202

Layer-specific cholinergic control of human and mouse cortical synaptic plasticity

Individual cortical layers have distinct roles in information processing. All layers receive cholinergic inputs from the basal forebrain (BF), which is crucial for cognition. Acetylcholinergic receptors are differentially distributed across cortical layers, and recent evidence suggests that different populations of BF cholinergic neurons may target specific prefrontal cortical (PFC) layers, raising the question of whether cholinergic control of the PFC is layer dependent. Here we address this issue and reveal dendritic mechanisms by which endogenous cholinergic modulation of synaptic plasticity is opposite in superficial and deep layers of both mouse and human neocortex. Our results show that in different cortical layers, spike timing-dependent plasticity is oppositely regulated by the activation of nicotinic acetylcholine receptors (nAChRs) either located on dendrites of principal neurons or on GABAergic interneurons. Thus, layer-specific nAChR expression allows functional layer-specific control of cortical processing and plasticity by the BF cholinergic system, which is evolutionarily conserved from mice to humans

Group I mGluR-mediated activation of martinotti cells inhibits local cortical circuitry in human cortex

Group I metabotropic glutamate receptors (mGluRs) mediate a range of signaling and plasticity processes in the brain and are of growing importance as potential therapeutic targets in clinical trials for neuropsychiatric and neurodevelopmental disorders (NDDs). Fundamental knowledge regarding the functional effects of mGluRs upon pyramidal neurons and interneurons is derived largely from rodent brain, and their effects upon human neurons are predominantly untested. We therefore addressed how group I mGluRs affect microcircuits in human neocortex. We show that activation of group I mGluRs elicits action potential firing in Martinotti cells, which leads to increased synaptic inhibition onto neighboring neurons. Some other interneurons, including fast-spiking interneurons, are depolarized but do not fire action potentials in response to group I mGluR activation. Furthermore, we confirm the existence of group I mGluR-mediated depression of excitatory synapses in human pyramidal neurons. We propose that the strong increase in inhibition and depression of excitatory synapses onto layer 2/3 pyramidal neurons upon group I mGluR activation likely results in a shift in the balance between excitation and inhibition in the human cortical network

Numerical data table

Numerical data from figures 1-5. The table contains cellular data for morphology, physiology and modelling used in the article

Human voltage-gated Na⁺ and K⁺ channel properties underlie sustained fast AP signaling

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.</p

Structural and functional specializations of human fast-spiking neurons support fast cortical signaling

Fast-spiking interneurons (FSINs) provide fast inhibition that synchronizes neuronal activity and is critical for cognitive function. Fast synchronization frequencies are evolutionary conserved in the expanded human neocortex despite larger neuron-to-neuron distances that challenge fast input-output transfer functions of FSINs. Here, we test in human neurons from neurosurgery tissue, which mechanistic specializations of human FSINs explain their fast-signaling properties in human cortex. With morphological reconstructions, multipatch recordings, and biophysical modeling, we find that despite threefold longer dendritic path, human FSINs maintain fast inhibition between connected pyramidal neurons through several mechanisms: stronger synapse strength of excitatory inputs, larger dendrite diameter with reduced complexity, faster AP initiation, and faster and larger inhibitory output, while Na+ current activation/inactivation properties are similar. These adaptations underlie short input-output delays in fast inhibition of human pyramidal neurons through FSINs, explaining how cortical synchronization frequencies are conserved despite expanded and sparse network topology of human cortex.</p