Biology subjects

Clark, J. K.

Publications and source records attributed to Clark, J. K..

3 recordsLinked to original sources

bioRxiv2026

Adolescent development accelerates responses to input in human neocortical neurons

Through childhood and adolescence, profound changes to the physiology of individual neurons accompany large-scale network changes in the mammalian neocortex. These physiological changes are well understood in rodent models but far less is known in the human neocortex. Here we combine patch-clamp electrophysiology and single-cell sequencing (Patch-Seq) in neurosurgically-resected pediatric human brain slices and age-matched mouse brain slices to elucidate the unique developmental trajectory of human neurons. We find that human Layer 2/3 pyramidal neurons show distinctive postnatal changes in neuronal physiology that align with the more directed, feedforward network architecture of human neocortex relative to the mouse. Human-specific changes to spike train dynamics include faster spike latencies and selective acceleration of early spiking. By applying linear modeling to our Patch-Seq data, we identify genes that predict physiological variation across single cells. This unbiased approach unexpectedly identifies BK-type calcium-activated potassium channels as key drivers of human postnatal changes in spike train dynamics between childhood and adolescence. We further test this pathway through pharmacology and computational modeling. Together, our results reveal novel mechanisms of postnatal maturation in human neocortical neurons and demonstrate a new application of Patch-Seq to uncover gene-physiology relationships at single-cell resolution.

neuroscience↗

bioRxiv2020

Control of E-S Potentiation at two different sites in the dendro-somatic axis

EPSP-Spike (E-S) Potentiation occurs alongside synaptic Long-Term Potentiation (LTP), both triggered by high-frequency synaptic stimulation (HFS). In this study, we confirm the earlier findings that E-S potentiation appears to be prevented by prior reduction of GABAA receptor-mediated inhibitory synaptic transmission. However, we demonstrate that this is a result of an occlusion of E-S potentiation, not a block. E-S potentiation and GABAA antagonism each saturate postsynaptic action potential discharge, but E-S potentiation can still be induced by high frequency activation of synapses, even in the presence of pharmacological GABAA blockade. These results suggest that GABAA blockers/antagonists and E-S potentiation share an expression mechanism, namely the reduction of GABAA-mediated synaptic inhibition. We also assayed changes in the electrical coupling between dendrite and soma, and were surprised to find that this coupling is decreased following HFS, a change that would oppose E-S potentiation. This decrease in dendritic-soma electrical coupling (D-S coupling) was induced through the action of GABAB receptors, but not maintained or expressed via the activity of these receptors. These data all together suggest that there are two distinct and opposing changes that occur as a result of HFS: 1) A decrease in passive dendro-somatic electrical coupling, and 2), an increase in coupling between the somatic EPSP and action potential generation. These two opposing influences may function as a homeostatic mechanism to balance the excitatory/inhibitory relationship between primary neurons and interneurons, and may represent a separate mechanism by which feedback and feed-forward synaptic inhibition can influence E-S coupling in opposite directions. Significance statementE-S Potentiation is an activity-dependent form of plasticity that boosts the efficiency of the coupling between synaptic input and action potential output in a neuron. Because it is induced by synaptic activity in series with the more familiar long-term potentiation (LTP), and is similarly persistent, it represents an additional mechanism by which memory traces may be stored within neural circuits. The significance of this paper is that it shows that there are at least two points of control for E-S potentiation which influence it in opposite directions, thereby providing additional basic mechanisms by which memory traces may be modulated.

neuroscience↗

bioRxiv2019

Differential Inhibition of E-S Potentiation and Long-term Potentiation by Cell-derived and Arctic Amyloid Beta

Soluble oligomers of amyloid-beta peptide (Abeta) have been implicated in the onset of memory deficits in Alzheimers disease, perhaps due to their reported ability to impair long-term potentiation (LTP) of synaptic strength. We previously showed the effect of Abeta on LTP depends on the strength of LTP induction. Furthermore, Abeta affects EPSP-Spike (E-S) potentiation more robustly than LTP, suggesting that E-S potentiation may be equally important to learning and memory in the context of Alzheimers disease. Here we extend our findings to two additional forms of Abeta that form higher concentrations of soluble Abeta oligomers and show that they also affect E-S potentiation at induction strengths where there is no effect on LTP in hippocampal slices.

neuroscience↗