Somatic HCN channels augment and speed up GABAergic basket cell input-output function in human neocortex

Neurons in the mammalian brain exhibit evolution-driven species-specific differences in their functional properties. Therefore, understanding the human brain requires unraveling the human neuron 'uniqueness' and how it contributes to the operation of specific neuronal circuits. We show here that a highly abundant type of inhibitory neurons in the neocortex, GABAergic parvalbumin-expressing basket cell (pv+BC), exhibits in the human brain a specific somatic leak current mechanism, which is absent in their rodent neuronal counterparts. Human pv+BC soma shows electric leak conductance mediated by hyperpolarization-activated cyclic nucleotide-gated channels. This leak conductance has depolarizing effects on the resting membrane potential and it accelerates the rise of synaptic potentials in the cell soma. The leak facilitates the human pv+BC input-to-output fidelity and shortens the action potential generation to excitatory inputs. This mechanism constitutes an adaptation that enhances signal transmission fidelity and speed in the common inhibitory circuit in the human but not in the rodent neocortex.

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Hyperpolarization-activated cyclic-nucleotide-gated channels potentially modulate axonal excitability at different thresholds

Journal of Neurophysiology ◽

10.1152/jn.00576.2017 ◽

2017 ◽

Vol 118 (6) ◽

pp. 3044-3050 ◽

Cited By ~ 2

Author(s):

Dinushi Weerasinghe ◽

Parvathi Menon ◽

Steve Vucic

Keyword(s):

Cyclic Nucleotide ◽

Neurological Diseases ◽

Lower Threshold ◽

Resting Membrane Potential ◽

Hcn Channels ◽

Motor Axons ◽

Cyclic Nucleotide Gated Channels ◽

Sensory Axons ◽

Current Threshold ◽

Axonal Excitability

Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels mediate differences in sensory and motor axonal excitability at different thresholds in animal models. Importantly, HCN channels are responsible for voltage-gated inward rectifying ( Ih) currents activated during hyperpolarization. The Ih currents exert a crucial role in determining the resting membrane potential and have been implicated in a variety of neurological disorders, including neuropathic pain. In humans, differences in biophysical properties of motor and sensory axons at different thresholds remain to be elucidated and could provide crucial pathophysiological insights in peripheral neurological diseases. Consequently, the aim of this study was to characterize sensory and motor axonal function at different threshold. Median nerve motor and sensory axonal excitability studies were undertaken in 15 healthy subjects (45 studies in total). Tracking targets were set to 20, 40, and 60% of maximum for sensory and motor axons. Hyperpolarizing threshold electrotonus (TEh) at 90–100 ms was significantly increased in lower threshold sensory axons times ( F = 11.195, P < 0.001). In motor axons, the hyperpolarizing current/threshold ( I/ V) gradient was significantly increased in lower threshold axons ( F = 3.191, P < 0.05). The minimum I/ V gradient was increased in lower threshold motor and sensory axons. In conclusion, variation in the kinetics of HCN isoforms could account for the findings in motor and sensory axons. Importantly, assessing the function of HCN channels in sensory and motor axons of different thresholds may provide insights into the pathophysiological processes underlying peripheral neurological diseases in humans, particularly focusing on the role of HCN channels with the potential of identifying novel treatment targets. NEW & NOTEWORTHY Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels, which underlie inward rectifying currents ( Ih), appear to mediate differences in sensory and motor axonal properties. Inward rectifying currents are increased in lower threshold motor and sensory axons, although different HCN channel isoforms appear to underlie these changes. While faster activating HCN channels seem to underlie Ih changes in sensory axons, slower activating HCN isoforms appear to be mediating the differences in Ih conductances in motor axons of different thresholds. The differences in HCN gating properties could explain the predilection for dysfunction of sensory and motor axons in specific neurological diseases.

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Insights into the Connectivity of the Human Brain Using DTI

Nepalese Journal of Radiology ◽

10.3126/njr.v1i1.6330 ◽

2012 ◽

Vol 1 (1) ◽

pp. 78-91 ◽

Cited By ~ 2

Author(s):

S Kollias

Keyword(s):

Human Brain ◽

Molecular Diffusion ◽

Diffusion Tensor ◽

Wide Spectrum ◽

Diffusion Imaging ◽

Structural Connectivity ◽

Nerve Tissue ◽

Mammalian Brain ◽

Fibre Direction

Diffusion tensor imaging (DTI) is a neuroimaging MR technique, which allows in vivo and non-destructive visualization of myeloarchitectonics in the neural tissue and provides quantitative estimates of WM integrity by measuring molecular diffusion. It is based on the phenomenon of diffusion anisotropy in the nerve tissue, in that water molecules diffuse faster along the neural fibre direction and slower in the fibre-transverse direction. On the basis of their topographic location, trajectory, and areas that interconnect the various fibre systems of the mammalian brain are divided into commissural, projectional and association fibre systems. DTI has opened an entirely new window on the white matter anatomy with both clinical and scientific applications. Its utility is found in both the localization and the quantitative assessment of specific neuronal pathways. The potential of this technique to address connectivity in the human brain is not without a few methodological limitations. A wide spectrum of diffusion imaging paradigms and computational tractography algorithms has been explored in recent years, which established DTI as promising new avenue, for the non-invasive in vivo mapping of structural connectivity at the macroscale level. Further improvements in the spatial resolution of DTI may allow this technique to be applied in the near future for mapping connectivity also at the mesoscale level. DOI: http://dx.doi.org/10.3126/njr.v1i1.6330 Nepalese Journal of Radiology Vol.1(1): 78-91

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Taste quality representation in the human brain

10.1101/726711 ◽

2019 ◽

Author(s):

Jason A. Avery ◽

Alexander G. Liu ◽

John E. Ingeholm ◽

Cameron D. Riddell ◽

Stephen J. Gotts ◽

...

Keyword(s):

Human Brain ◽

Cortical Neurons ◽

Brain Regions ◽

Taste Quality ◽

7 Tesla ◽

Mammalian Brain ◽

High Magnetic Field Strength ◽

Magnetic Resonance Imaging Mri ◽

Spatial Locations ◽

Univariate Analyses

SUMMARYIn the mammalian brain, the insula is the primary cortical substrate involved in the perception of taste. Recent imaging studies in rodents have identified a gustotopic organization in the insula, whereby distinct insula regions are selectively responsive to one of the five basic tastes. However, numerous studies in monkeys have reported that gustatory cortical neurons are broadly-tuned to multiple tastes, and tastes are not represented in discrete spatial locations. Neuroimaging studies in humans have thus far been unable to discern between these two models, though this may be due to the relatively low spatial resolution employed in taste studies to date. In the present study, we examined the spatial representation of taste within the human brain using ultra-high resolution functional magnetic resonance imaging (MRI) at high magnetic field strength (7-Tesla). During scanning, participants tasted sweet, salty, sour and tasteless liquids, delivered via a custom-built MRI-compatible tastant-delivery system. Our univariate analyses revealed that all tastes (vs. tasteless) activated primary taste cortex within the bilateral dorsal mid-insula, but no brain region exhibited a consistent preference for any individual taste. However, our multivariate searchlight analyses were able to reliably decode the identity of distinct tastes within those mid-insula regions, as well as brain regions involved in affect and reward, such as the striatum, orbitofrontal cortex, and amygdala. These results suggest that taste quality is not represented topographically, but by a combinatorial spatial code, both within primary taste cortex as well as regions involved in processing the hedonic and aversive properties of taste.

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Neuronal and Astrocytic Regulations in Schizophrenia: A Computational Modelling Study

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.718459 ◽

2021 ◽

Vol 15 ◽

Author(s):

Lea Fritschi ◽

Johanna Hedlund Lindmar ◽

Florian Scheidl ◽

Kerstin Lenk

Keyword(s):

Computational Models ◽

Glutamate Release ◽

Signal Transmission ◽

Computational Modelling ◽

Atp Release ◽

Network Activity ◽

Inhibitory Neurons ◽

Neuronal Network Activity ◽

Cell Densities ◽

Synapse Model

According to the tripartite synapse model, astrocytes have a modulatory effect on neuronal signal transmission. More recently, astrocyte malfunction has been associated with psychiatric diseases such as schizophrenia. Several hypotheses have been proposed on the pathological mechanisms of astrocytes in schizophrenia. For example, post-mortem examinations have revealed a reduced astrocytic density in patients with schizophrenia. Another hypothesis suggests that disease symptoms are linked to an abnormality of glutamate transmission, which is also regulated by astrocytes (glutamate hypothesis of schizophrenia). Electrophysiological findings indicate a dispute over whether the disorder causes an increase or a decrease in neuronal and astrocytic activity. Moreover, there is no consensus as to which molecular pathways and network mechanisms are altered in schizophrenia. Computational models can aid the process in finding the underlying pathological malfunctions. The effect of astrocytes on the activity of neuron-astrocyte networks has been analysed with computational models. These can reproduce experimentally observed phenomena, such as astrocytic modulation of spike and burst signalling in neuron-astrocyte networks. Using an established computational neuron-astrocyte network model, we simulate experimental data of healthy and pathological networks by using different neuronal and astrocytic parameter configurations. In our simulations, the reduction of neuronal or astrocytic cell densities yields decreased glutamate levels and a statistically significant reduction in the network activity. Amplifications of the astrocytic ATP release toward postsynaptic terminals also reduced the network activity and resulted in temporarily increased glutamate levels. In contrast, reducing either the glutamate release or re-uptake in astrocytes resulted in higher network activities. Similarly, an increase in synaptic weights of excitatory or inhibitory neurons raises the excitability of individual cells and elevates the activation level of the network. To conclude, our simulations suggest that the impairment of both neurons and astrocytes disturbs the neuronal network activity in schizophrenia.

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Mg2+ is a Missing Link in Plant Cell Ca2+ Signalling and Homeostasis—A Study on Vicia faba Guard Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21113771 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3771

Author(s):

Fouad Lemtiri-Chlieh ◽

Stefan T. Arold ◽

Chris Gehring

Keyword(s):

Plant Cell ◽

Guard Cells ◽

Cell Types ◽

K Channel ◽

Resting Membrane Potential ◽

Binding Motif ◽

Animal Cells ◽

Membrane Hyperpolarization ◽

Cyclic Nucleotide Gated Channels ◽

Channel Opening

Hyperpolarization-activated calcium channels (HACCs) are found in the plasma membrane and tonoplast of many plant cell types, where they have an important role in Ca2+-dependent signalling. The unusual gating properties of HACCs in plants, i.e., activation by membrane hyperpolarization rather than depolarization, dictates that HACCs are normally open in the physiological hyperpolarized resting membrane potential state (the so-called pump or P-state); thus, if not regulated, they would continuously leak Ca2+ into cells. HACCs are permeable to Ca2+, Ba2+, and Mg2+; activated by H2O2 and the plant hormone abscisic acid (ABA); and their activity in guard cells is greatly reduced by increasing amounts of free cytosolic Ca2+ ([Ca2+]Cyt), and hence closes during [Ca2+]Cyt surges. Here, we demonstrate that the presence of the commonly used Mg-ATP inside the guard cell greatly reduces HACC activity, especially at voltages ≤ −200 mV, and that Mg2+ causes this block. Therefore, we firstly conclude that physiological cytosolic Mg2+ levels affect HACC gating and that channel opening requires either high negative voltages (≥−200 mV) or displacement of Mg2+ away from the immediate vicinity of the channel. Secondly, based on structural comparisons with a Mg2+-sensitive animal inward-rectifying K+ channel, we propose that the likely candidate HACCs described here are cyclic nucleotide gated channels (CNGCs), many of which also contain a conserved diacidic Mg2+ binding motif within their pores. This conclusion is consistent with the electrophysiological data. Finally, we propose that Mg2+, much like in animal cells, is an important component in Ca2+ signalling and homeostasis in plants.

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Monoclonal antibodies against a C-terminal peptide of human brain acetylcholinesterase distinguish between erythrocyte and brain acetylcholinesterases

Clinical Chemistry ◽

10.1093/clinchem/42.1.19 ◽

1996 ◽

Vol 42 (1) ◽

pp. 19-23 ◽

Cited By ~ 4

Author(s):

N Boschetti ◽

U Brodbeck ◽

S P Jensen ◽

C Koch ◽

B Nørgaard-Pedersen

Keyword(s):

Monoclonal Antibodies ◽

Human Brain ◽

Solid Phase ◽

Bovine Brain ◽

Mammalian Brain ◽

Dot Blot ◽

Electric Eel ◽

Terminal Amino ◽

Dot Blot Analysis ◽

Brain Acetylcholinesterase

Abstract Monoclonal antibodies (mAbs) were raised against a peptide of the 10 C-terminal amino acids of human brain acetylcholinesterase (AChE): H-Tyr-Ser-Lys-Gln-Asp-Arg-Cys-Ser-Asp-Leu-OH. Two positive clones (mAbs 190-1 and 190-2) were selected and tested for their ability to distinguish between mammalian brain and erythrocyte AChEs. In a solid-phase enzyme antigen immunoassay as well as by Western- and dot-blot analysis, both antibodies showed clear binding to AChE from human and bovine brain but not to AChE from erythrocytes. MAbs 190-1 and 190-2 reacted with neither AChE from electric eel nor butyrylcholinesterase from human serum. Both antibodies were used in a quantitative assay for AChE in amniotic fluids, where AChE activity could be found only in samples from open neural tube-defect pregnancies, but not in fluids from normal pregnancies or in artificially blood-contaminated samples.

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High-conductance states and A-type K+ channels are potential regulators of the conductance-current balance triggered by HCN channels

Journal of Neurophysiology ◽

10.1152/jn.00601.2013 ◽

2015 ◽

Vol 113 (1) ◽

pp. 23-43 ◽

Cited By ~ 21

Author(s):

Poonam Mishra ◽

Rishikesh Narayanan

Keyword(s):

Dominant Role ◽

Input Resistance ◽

Resting Membrane Potential ◽

Voltage Response ◽

Hcn Channels ◽

Type K ◽

Conductance States ◽

The Impact ◽

High Conductance

An increase in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel conductance reduces input resistance, whereas the consequent increase in the inward h current depolarizes the membrane. This results in a delicate and unique conductance-current balance triggered by the expression of HCN channels. In this study, we employ experimentally constrained, morphologically realistic, conductance-based models of hippocampal neurons to explore certain aspects of this conductance-current balance. First, we found that the inclusion of an experimentally determined gradient in A-type K+ conductance, but not in M-type K+ conductance, tilts the HCN conductance-current balance heavily in favor of conductance, thereby exerting an overall restorative influence on neural excitability. Next, motivated by the well-established modulation of neuronal excitability by synaptically driven high-conductance states observed under in vivo conditions, we inserted thousands of excitatory and inhibitory synapses with different somatodendritic distributions. We measured the efficacy of HCN channels, independently and in conjunction with other channels, in altering resting membrane potential (RMP) and input resistance ( Rin) when the neuron received randomized or rhythmic synaptic bombardments through variable numbers of synaptic inputs. We found that the impact of HCN channels on average RMP, Rin, firing frequency, and peak-to-peak voltage response was severely weakened under high-conductance states, with the impinging synaptic drive playing a dominant role in regulating these measurements. Our results suggest that the debate on the role of HCN channels in altering excitability should encompass physiological and pathophysiological neuronal states under in vivo conditions and the spatiotemporal interactions of HCN channels with other channels.

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Hyperpolarization-activated cyclic nucleotide-gated channels in peripheral diaphragmatic lymphatics

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00193.2016 ◽

2016 ◽

Vol 311 (4) ◽

pp. H892-H903 ◽

Cited By ~ 15

Author(s):

Daniela Negrini ◽

Cristiana Marcozzi ◽

Eleonora Solari ◽

Elena Bossi ◽

Raffaella Cinquetti ◽

...

Keyword(s):

Cyclic Nucleotide ◽

Cesium Chloride ◽

Spontaneous Contraction ◽

Hcn Channels ◽

Contraction Frequency ◽

Cyclic Nucleotide Gated Channels ◽

Perfusion Chamber ◽

Molecular Machinery ◽

Pressure Changes ◽

Zd 7288

Diaphragmatic lymphatic function is mainly sustained by pressure changes in the tissue and serosal cavities during cardiorespiratory cycles. The most peripheral diaphragmatic lymphatics are equipped with muscle cells (LMCs), which exhibit spontaneous contraction, whose molecular machinery is still undetermined. Hypothesizing that spontaneous contraction might involve hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in lymphatic LMCs, diaphragmatic specimens, including spontaneously contracting lymphatics, were excised from 33 anesthetized rats, moved to a perfusion chamber containing HEPES-Tyrode's solution, and treated with HCN channels inhibitors cesium chloride (CsCl), ivabradine, and ZD-7288. Compared with control, exposure to 10 mM CsCl reduced (−65%, n = 13, P < 0.01) the contraction frequency (FL) and increased end-diastolic diameter (DL-d, +7.3%, P < 0.01) without changes in end-systolic diameter (DL-s). Ivabradine (300 μM) abolished contraction and increased DL-d (−14%, n = 10, P < 0.01) or caused an incomplete inhibition of FL ( n = 3, P < 0.01), leaving DL-d and DL-s unaltered. ZD-7288 (200 μM) completely ( n = 12, P < 0.01) abolished FL, while DL-d decreased to 90.9 ± 2.7% of control. HCN gene expression and immunostaining confirmed the presence of HCN1-4 channel isoforms, likely arranged in different configurations, in LMCs. Hence, all together, data suggest that HCN channels might play an important role in affecting contraction frequency of LMCs.

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Effect of presynaptic membrane potential on electrical vs. chemical synaptic transmission

Journal of Neurophysiology ◽

10.1152/jn.00340.2011 ◽

2011 ◽

Vol 106 (2) ◽

pp. 680-689 ◽

Cited By ~ 2

Author(s):

Colin G. Evans ◽

Bjoern Ch. Ludwar ◽

Timothy Kang ◽

Elizabeth C. Cropper

Keyword(s):

Membrane Potential ◽

Synaptic Transmission ◽

Electrical Coupling ◽

Mammalian Brain ◽

Resting Membrane Potential ◽

Presynaptic Membrane ◽

Electrical Transmission ◽

A Cell ◽

Peripheral Activation ◽

Chemical Transmission

The growing realization that electrical coupling is present in the mammalian brain has sparked renewed interest in determining its functional significance and contrasting it with chemical transmission. One question of interest is whether the two types of transmission can be selectively regulated, e.g., if a cell makes both types of connections can electrical transmission occur in the absence of chemical transmission? We explore this issue in an experimentally advantageous preparation. B21, the neuron we study, is an Aplysia sensory neuron involved in feeding that makes electrical and chemical connections with other identified cells. Previously we demonstrated that chemical synaptic transmission is membrane potential dependent. It occurs when B21 is centrally depolarized prior to and during peripheral activation, but does not occur if B21 is peripherally activated at its resting membrane potential. In this article we study effects of membrane potential on electrical transmission. We demonstrate that maximal potentiation occurs in different voltage ranges for the two types of transmission, with potentiation of electrical transmission occurring at more hyperpolarized potentials (i.e., requiring less central depolarization). Furthermore, we describe a physiologically relevant type of stimulus that induces both spiking and an envelope of depolarization in the somatic region of B21. This depolarization does not induce functional chemical synaptic transmission but is comparable to the depolarization needed to maximally potentiate electrical transmission. In this study we therefore characterize a situation in which electrical and chemical transmission can be selectively controlled by membrane potential.

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Xenotransplanted human cortical neurons reveal species-specific development and functional integration into mouse visual circuits

10.1101/626218 ◽

2019 ◽

Cited By ~ 2

Author(s):

Daniele Linaro ◽

Ben Vermaercke ◽

Ryohei Iwata ◽

Arjun Ramaswamy ◽

Brittany A. Davis ◽

...

Keyword(s):

Visual Cortex ◽

Human Brain ◽

Cortical Neurons ◽

Single Cells ◽

Functional Integration ◽

List Type ◽

Visual Responses ◽

Mouse Cortex ◽

Human Neurons ◽

Species Specific

SummaryHow neural circuits develop in the human brain has remained almost impossible to study at the neuronal level. Here we investigate human cortical neuron development, plasticity and function, using a mouse/human chimera model in which xenotransplanted human cortical pyramidal neurons integrate as single cells into the mouse cortex. Combined neuronal tracing, electrophysiology, andin vivostructural and functional imaging revealed that the human neurons develop morphologically and functionally following a prolonged developmental timeline, revealing the cell-intrinsic retention of juvenile properties of cortical neurons as an important mechanism underlying human brain neoteny. Following maturation, human neurons transplanted in the visual cortex display tuned responses to visual stimuli that are similar to those of mouse neurons, indicating capacity for physiological synaptic integration of human neurons in mouse cortical circuits. These findings provide new insights into human neuronal development, and open novel experimental avenues for the study of human neuronal function and diseases.Highlights:Coordinated morphological and functional maturation of ESC-derived human cortical neurons transplanted in the mouse cortex.Transplanted neurons display prolonged juvenile features indicative of intrinsic species-specific neoteny.Transplanted neurons develop elaborate dendritic arbors, stable spine patterns and long-term synaptic plasticity.In the visual cortex transplanted neurons display tuned visual responses that resemble those of the host cortical neurons.

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