Age-dependent increased sag amplitude in human pyramidal neurons dampens baseline cortical activity

Guet-McCreight, Alexandre; Chameh, Homeira Moradi; Mahallati, Sara; Wishart, Margaret; Tripathy, Shreejoy J.; Valiante, Taufik A.; Hay, Etay

doi:10.1093/cercor/bhac348

Cited by 19 publications

(19 citation statements)

References 81 publications

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“…One possible explanation is that this may allow for faster and more efficient regulation of somatic excitability and resting membrane potential in the human neurons. Our results and previous studies demonstrate that modulation of HCN channel activity or expression at the soma can powerfully regulate intrinsic excitability and firing fidelity [ 42 , 44 , 47 , 52 , 89 – 90 ]. In some neuron types, HCN channel activity can be rapidly up- or down-regulated by second messenger cascades initiated by neuronal excitation and activity [ 8 , 45 , 71 ].…”

Section: Discussionsupporting

confidence: 74%

“…Moreover, the two key characteristics governing human fast-spiking basket cell excitability, high input resistance at the cell soma and a large HCN channel-mediated somatic voltage sag, have also been reported in fast-spiking interneurons of macaque monkey neocortex [ 40 , 41 , 54 ], suggesting that small persistent ion leak with robust HCN channel activity is a common adaptation of fast-spiking neurons in primates [ 64 ]. Human cortical pyramidal cells also exhibit a stronger sag potential and higher somatic HCN expression than rodent cortical pyramidal cells [ 21 , 47 ]. Thus, it appears that multiple human cortical neuron types employ robust somatic HCN channels.…”

Section: Discussionmentioning

confidence: 99%

“…RNA sequencing studies and proteome analyses show high levels of HCN channel isoforms HCN1 and HCN2 in the human and rodent neocortex [21,46]. However, recent electrophysiological studies utilizing surgically resected human brain tissue have shown that HCN channel activity in human neocortex excitatory neurons is much stronger than in their mouse analogs compared to their mouse analogues, and this difference is particularly large at the cell soma [21,24,47]. In rodent pv interneurons, HCN channels are predominantly expressed at the axon [46,48] where they remotely regulate firing frequency and neurotransmitter release [49][50][51]; however, they are largely or completely absent from the pv cell soma in the neocortex [40][41][42][52][53][54][55].…”

Section: Introductionmentioning

confidence: 99%

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HCN channels at the cell soma ensure the rapid electrical reactivity of fast-spiking interneurons in human neocortex

et al. 2023

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Accumulating evidence indicates that there are substantial species differences in the properties of mammalian neurons, yet theories on circuit activity and information processing in the human brain are based heavily on results obtained from rodents and other experimental animals. This knowledge gap may be particularly important for understanding the neocortex, the brain area responsible for the most complex neuronal operations and showing the greatest evolutionary divergence. Here, we examined differences in the electrophysiological properties of human and mouse fast-spiking GABAergic basket cells, among the most abundant inhibitory interneurons in cortex. Analyses of membrane potential responses to current input, pharmacologically isolated somatic leak currents, isolated soma outside-out patch recordings, and immunohistochemical staining revealed that human neocortical basket cells abundantly express hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel isoforms HCN1 and HCN2 at the cell soma membrane, whereas these channels are sparse at the rodent basket cell soma membrane. Antagonist experiments showed that HCN channels in human neurons contribute to the resting membrane potential and cell excitability at the cell soma, accelerate somatic membrane potential kinetics, and shorten the lag between excitatory postsynaptic potentials and action potential generation. These effects are important because the soma of human fast-spiking neurons without HCN channels exhibit low persistent ion leak and slow membrane potential kinetics, compared with mouse fast-spiking neurons. HCN channels speed up human cell membrane potential kinetics and help attain an input–output rate close to that of rodent cells. Computational modeling demonstrated that HCN channel activity at the human fast-spiking cell soma membrane is sufficient to accelerate the input–output function as observed in cell recordings. Thus, human and mouse fast-spiking neurons exhibit functionally significant differences in ion channel composition at the cell soma membrane to set the speed and fidelity of their input–output function. These HCN channels ensure fast electrical reactivity of fast-spiking cells in human neocortex.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HCN channels at the cell soma ensure the rapid electrical reactivity of fast-spiking interneurons in human neocortex

et al. 2023

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“…Further support for the predictive power of the L2/3 microcircuits stems from L2/3 being closest to the EEG electrode and thus primary contributor to EEG signals (Buzsáki, Anastassiou, and Koch 2012). Future expanded models that include layers 4 and 5 could help refine our estimated EEG biomarkers of α5-PAM effects, by including the additional complexities of interlaminar oscillatory communication (Florez et al 2015) as well as oscillatory dynamics present in deeper cortical layers (Guet-McCreight et al 2022; Roopun et al 2006). We do, however, expect our biomarkers will largely hold, so that any refinements will rather serve to provide additional biomarkers such as phase-amplitude coupling between different frequency bands originating from different layers (Florez et al 2015).…”

Section: Discussionmentioning

confidence: 99%

In-silico testing of new pharmacology for restoring inhibition and human cortical function in depression

Guet-McCreight

Moradi-Chameh

Mazza

et al. 2023

Preprint

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Reduced inhibition by somatostatin-expressing interneurons is associated with depression. Administration of positive allosteric modulators of α5 subunit-containing GABAA receptor (α5-PAM) that selectively target this lost inhibition exhibit antidepressant and pro-cognitive effects in rodent models of chronic stress. However, the functional effects of α5-PAM on the human brain in vivo are unknown, and currently cannot be assessed experimentally. We modeled the effects of α5-PAM on tonic inhibition as measured in human neurons, and tested in silico α5-PAM effects on detailed models of human cortical microcircuits in health and depression. We found that α5-PAM effectively recovered impaired cortical processing as quantified by stimulus detection metrics, and also recovered the power spectral density profile of the microcircuit EEG signals. We performed an α5-PAM dose response and identified simulated EEG biomarkers. Our results serve to de-risk and facilitate α5-PAM translation and provide biomarkers in non-invasive brain signals for monitoring target engagement and drug efficacy.

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“…Resected neocortical tissue samples provide highly relevant material for human neuron aging investigation because noninvasive brain scan studies, behavioral tests, and anatomical postmortem analyses show that aging affects the neocortex in various ways (Peters, 2006; Rozycka and Liguz-Lecznar, 2017; Sibille, 2013). However, to the best of our knowledge, only a few studies have investigated electrophysiological changes in neurons in the human brain during senescence (Guet-McCreight et al, 2023; Pegasiou et al, 2020; Popov et al, 2023; Testa-Silva et al, 2014; Wang et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Aging-associated weakening of the action potential in fast-spiking interneurons in the human neocortex

Szegedi,

Tiszlavicz,

Furdan

et al. 2024

Preprint

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Aging is associated with the slowdown of neuronal processing and cognitive performance in the brain; however, the exact cellular mechanisms behind this deterioration in humans are poorly elucidated. Recordings in human acute brain slices prepared from tissue resected during brain surgery enable the investigation of neuronal changes with age. Although neocortical fast-spiking cells are widely implicated in neuronal network activities underlying cognitive processes, they are vulnerable to neurodegeneration. Herein, we analyzed the electrical properties of 147 fast-spiking interneurons in neocortex samples resected in brain surgery from 106 patients aged 11–84 years. By studying the electrophysiological features of action potentials and passive membrane properties, we report that action potential overshoot significantly decreases and spike half-width increases with age. Moreover, the action potential maximum-rise speed (but not the repolarization speed or the afterhyperpolarization amplitude) significantly changed with age, suggesting a particular weakening of the sodium channel current generated in the soma. Cell passive membrane properties measured as the input resistance, membrane time constant, and cell capacitance remained unaffected by senescence. Thus, we conclude that the action potential in fast-spiking interneurons shows a significant weakening in the human neocortex with age. This may contribute to the deterioration of cortical functions by aging.

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Age-dependent increased sag amplitude in human pyramidal neurons dampens baseline cortical activity

Cited by 19 publications

References 81 publications

HCN channels at the cell soma ensure the rapid electrical reactivity of fast-spiking interneurons in human neocortex

HCN channels at the cell soma ensure the rapid electrical reactivity of fast-spiking interneurons in human neocortex

In-silico testing of new pharmacology for restoring inhibition and human cortical function in depression

Aging-associated weakening of the action potential in fast-spiking interneurons in the human neocortex

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