Biology subjects

de Witt Hamer, P. C.

Publications and source records attributed to de Witt Hamer, P. C..

4 recordsLinked to original sources

bioRxiv2022

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 surprisingly 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. Finally, 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. One-Sentence SummaryBiophysical properties of Na+ and K+ ion channels enable human neurons to reliably encode fast inputs into output.

neuroscience↗

bioRxiv2022

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. Teaser/one-sentence summarySpecializations of fast spiking human neurons ensure fast signaling in human cortex.

neuroscience↗

bioRxiv2021

Expansion of cortical layers 2 and 3 in human left temporal cortex associates with verbal intelligence

The expansion of supragranular cortical layers is thought to have enabled evolutionary development of human cognition and language. However, whether increased volume of supragranular cortical layers can actually support greater cognitive and language abilities in humans has not been demonstrated. Here, we find that subjects with higher general and verbal intelligence test (VIQ) scores have selectively expanded layers 2 and 3 only in the left temporal cortex, an area associated with language and IQ-test performance. This expansion is accompanied by lower neuron densities and larger cell-body size. Furthermore, individuals with higher VIQ scores had neurons with larger dendritic trees in left temporal cortex, potentially impacting their function. Indeed, neurons of subjects with higher VIQ scores had faster action potential upstroke kinetics, which improves information processing. These data show that expansion of supragranular layer volume, cortical and cellular micro-architecture and function are associated with improved verbal mental ability in human subjects.

neuroscience↗

bioRxiv2021

Neuronal morphology and physiology, functional brain networks and memory in temporal lobe epilepsy

Temporal lobe epilepsy (TLE) patients are at risk of memory deficits, which have been linked to functional network disturbances, particularly of integration of the default mode network (DMN). However, the cellular substrates of functional network integration are unknown. We leverage a unique cross-scale dataset of therapy-resistant TLE patients, who underwent fMRI, MEG and/or neuropsychological testing before neurosurgery. fMRI and MEG underwent atlas-based connectivity analyses. Functional network centrality of the lateral middle temporal gyrus, part of the DMN, was used as a measure of local network integration. Subsequently, non-pathological cortical tissue from this region was used for single cell morphological and electrophysiological patch-clamp analysis, assessing integration in terms of total dendritic length and action potential rise speed. As could be hypothesized, greater network centrality related to better memory performance. Moreover, greater network centrality correlated with more integrative properties at the cellular level across patients. We conclude that individual differences in cognitively relevant functional network integration of a DMN region are mirrored by differences in cellular integrative properties of this region in TLE patients. These findings connect previously separate scales of investigation, increasing translational insight into focal pathology and large-scale network disturbances in TLE.

neuroscience↗