scholarly journals Biophysical basis of alpha rhythm disruption in Alzheimer’s disease

2018 ◽  
Author(s):  
Rohan Sharma ◽  
Suhita Nadkarni
Keyword(s):  
Alpha Rhythm ◽  
Symptomatic Relief ◽  
Acetylcholinesterase Inhibitors ◽  
Network Activity ◽  
Hcn Channels ◽  
Small Range ◽  
Cyclic Nucleotide Gated Channels ◽  
Calcium Ion Channels ◽  
Ion Channel Properties ◽  
Cortical Circuit

AbstractAlpha is one of the most prominent rhythms (7.5–12.5 Hz) detected in electroencephalography (EEG) during wakeful relaxation with closed eyes. In response to elevated ambient acetylcholine levels, a subclass of thalamic pacemaker cells generate alpha. This rhythm is intrinsic to the cell and is robustly orchestrated by an interplay of hyperpolarization activated cyclic nucleotide gated channels(HCN) and calcium-ion channels. It has been shown that decreased expression of HCN channels is correlated to Alzheimer's Diseased (AD). In early stages of AD, alpha is known to be down-regulated and lowered in coherence. We use this well characterized and quantified rhythm to understand the changes in ion channel properties that lead to disruption of alpha as seen in AD in a biophysically detailed network model of the thalamo-cortical circuit that generates the alpha-rhythm. Our computational model allows us to explore the causal links between alpha rhythms, HCN channels and amyloid-beta aggregation. The most commonly used drugs(acetylcholinesterase inhibitors) in AD increase the duration and level of acetylcholine and provide temporary symptomatic relief in some cases. Our simulations show how increasing acetylcholine can provide rescue for a small range of aberrant HCN expression. We hypothesize that reduced alpha rhythm frequency and coherence is a result of down-regulated HCN expression, rather then compromised cholinergic modulation(as is currently thought). The model predicts that lowering of the alpha-rhythm can modify the network activity in the thalamo-cortical circuit and lead to an increase in the inhibitory drive to the thalamus.

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

2017 ◽  
Vol 118 (6) ◽  
pp. 3044-3050 ◽  
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.

scholarly journals Inferring circuit mechanisms from sparse neural recording and global perturbation in grid cells

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
John Widloski ◽  
Michael P Marder ◽  
Ila R Fiete
Keyword(s):  
Grid Cell ◽  
Neural Recording ◽  
Cell System ◽  
Network Activity ◽  
Connectivity Matrix ◽  
Neural Recordings ◽  
Systems Neuroscience ◽  
Global Circuit ◽  
Full Knowledge ◽  
Cortical Circuit

A goal of systems neuroscience is to discover the circuit mechanisms underlying brain function. Despite experimental advances that enable circuit-wide neural recording, the problem remains open in part because solving the ‘inverse problem’ of inferring circuity and mechanism by merely observing activity is hard. In the grid cell system, we show through modeling that a technique based on global circuit perturbation and examination of a novel theoretical object called the distribution of relative phase shifts (DRPS) could reveal the mechanisms of a cortical circuit at unprecedented detail using extremely sparse neural recordings. We establish feasibility, showing that the method can discriminate between recurrent versus feedforward mechanisms and amongst various recurrent mechanisms using recordings from a handful of cells. The proposed strategy demonstrates that sparse recording coupled with simple perturbation can reveal more about circuit mechanism than can full knowledge of network activity or the synaptic connectivity matrix.

scholarly journals Decreased hyperpolarization-activated currents in layer 5 pyramidal neurons enhances excitability in focal cortical dysplasia

2011 ◽  
Vol 106 (5) ◽  
pp. 2189-2200 ◽  
Author(s):  
Asher J. Albertson ◽  
Jianming Yang ◽  
John J. Hablitz
Keyword(s):  
Pyramidal Neurons ◽  
Focal Cortical Dysplasia ◽  
Cortical Dysplasia ◽  
Network Activity ◽  
Hcn Channels ◽  
Excitatory Postsynaptic Potential ◽  
Patch Clamp Recording ◽  
Voltage Sensitive Dye ◽  
Whole Cell Patch Clamp ◽  
Voltage Sensitive Dye Imaging

Focal cortical dysplasia is associated with the development of seizures in children and is present in up to 40% of intractable childhood epilepsies. Transcortical freeze lesions in newborn rats reproduce many of the anatomical and physiological characteristics of human cortical dysplasia. Rats with freeze lesions have increased seizure susceptibility and a region of hyperexcitable cortex adjacent to the lesion. Since alterations in hyperpolarization-activated nonspecific cation (HCN) channels are often associated with epilepsy, we used whole cell patch-clamp recording and voltage-sensitive dye imaging to examine alterations in HCN channels and inwardly rectifying hyperpolarization-activated currents ( Ih) in cortical dysplasia. (L5) pyramidal neurons in lesioned animals had hyperpolarized resting membrane potentials, increased input resistances and reduced voltage “sag” associated with Ih activation. These differences became nonsignificant after application of the Ih blocker ZD7288. Temporal excitatory postsynaptic potential (EPSP) summation and intrinsic excitability were increased in neurons near the freeze lesion. Using voltage-sensitive dye imaging of neocortical slices, we found that inhibiting Ih with ZD7288 increased the half-width of dye signals. The anticonvulsant lamotrigine produced a significant decrease in spread of activity. The ability of lamotrigine to decrease network activity was reduced in the hyperexcitable cortex near the freeze lesion. These results suggest that Ih serves to constrain network activity in addition to its role in regulating cellular excitability. Reduced Ih may contribute to increased network excitability in cortical dysplasia.

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

2016 ◽  
Vol 311 (4) ◽  
pp. H892-H903 ◽  
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.

scholarly journals Untangling stability and gain modulation in cortical circuits with multiple interneuron classes

2020 ◽  
Author(s):  
Hannah Bos ◽  
Anne-Marie Oswald ◽  
Brent Doiron
Keyword(s):  
Pyramidal Neurons ◽  
Mean Field ◽  
Gain Control ◽  
Cell Types ◽  
High Gain ◽  
Cortical Inhibition ◽  
Network Activity ◽  
Inhibitory Neurons ◽  
Neuron Models ◽  
Cortical Circuit

AbstractSynaptic inhibition is the mechanistic backbone of a suite of cortical functions, not the least of which is maintaining overall network stability as well as modulating neuronal gain. Past cortical models have assumed simplified recurrent networks in which all inhibitory neurons are lumped into a single effective pool. In such models the mechanics of inhibitory stabilization and gain control are tightly linked in opposition to one another – meaning high gain coincides with low stability and vice versa. This tethering of stability and response gain restricts the possible operative regimes of the network. However, it is now well known that cortical inhibition is very diverse, with molecularly distinguished cell classes having distinct positions within the cortical circuit. In this study, we analyze populations of spiking neuron models and associated mean-field theories capturing circuits with pyramidal neurons as well as parvalbumin (PV) and somatostatin (SOM) expressing interneurons. Our study outlines arguments for a division of labor within the full cortical circuit where PV interneurons are ideally positioned to stabilize network activity, whereas SOM interneurons serve to modulate pyramidal cell gain. This segregation of inhibitory function supports stable cortical dynamics over a large range of modulation states. Our study offers a blueprint for how to relate the circuit structure of cortical networks with diverse cell types to the underlying population dynamics and stimulus response.

scholarly journals Simulation and calculation of the contribution of hyperpolarization-activated cyclic nucleotide-gated channels to action potentials

2016 ◽  
Vol 68 (1) ◽  
pp. 217-224
Author(s):  
Liping Liao ◽  
Xianguang Lin ◽  
Jielin Hu ◽  
Xin Wu ◽  
Xiaofei Yang ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Action Potential ◽  
Cyclic Nucleotide ◽  
Ganglion Cells ◽  
Recovery Phase ◽  
Hcn Channels ◽  
Action Potential Generation ◽  
Hcn Channel ◽  
Potential Generation ◽  
Cyclic Nucleotide Gated Channels

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel, which mediates the influx of cations, has an important role in action potential generation. In this article, we describe the contribution of the HCN channel to action potential generation. We simulated several common ion channels in neuron membranes based on data from rat dorsal root ganglion cells and modeled the action potential. The ion channel models employed in this paper were based on the Markov model. After modifying and calibrating these models, we compared the simulated action potential curves under the presence and absence of an HCN channel and calculated that the proportional contribution of the HCN channel in the potential recovery phase was 33.39%. This result indicates that the HCN channel is critical in assisting membrane potential recovery from a hyperpolarized state to a resting state. Furthermore, we showed how the HCN channel modifies the firing of the action potential using mathematic modeling. Our results indicated that although the loss of the HCN channel made recovery of the membrane potential more difficult from the most negative point to resting in comparison with the control, the firing rate of the action potential increased in certain circumstances. We present a novel explanation for the HCN channels? mechanism in neuron action potential generation using mathematical models.

scholarly journals Sex-Specific Cannabidiol- and Iloperidone-Induced Neuronal Activity Changes in an In Vitro MAM Model System of Schizophrenia

2021 ◽  
Vol 22 (11) ◽  
pp. 5511
Author(s):  
Rachel-Karson Thériault ◽  
Myles St-Denis ◽  
Tristen Hewitt ◽  
Jibran Y. Khokhar ◽  
Jasmin Lalonde ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Neuronal Activity ◽  
Underlying Mechanism ◽  
Network Activity ◽  
Antipsychotic Therapy ◽  
Sex Effects ◽  
Activity Measurements ◽  
Cortical Circuit ◽  
Bursting Activity

Cortical circuit dysfunction is thought to be an underlying mechanism of schizophrenia (SZ) pathophysiology with normalization of aberrant circuit activity proposed as a biomarker for antipsychotic efficacy. Cannabidiol (CBD) shows potential as an adjunctive antipsychotic therapy; however, potential sex effects in these drug interactions remain unknown. In the present study, we sought to elucidate sex effects of CBD coadministration with the atypical antipsychotic iloperidone (ILO) on the activity of primary cortical neuron cultures derived from the rat methylazoxymethanol acetate (MAM) model used for the study of SZ. Spontaneous network activity measurements were obtained using a multielectrode array at baseline and following administration of CBD or ILO alone, or combined. At baseline, MAM male neurons displayed increased bursting activity whereas MAM female neurons exhibited no difference in bursting activity compared to sex-matched controls. CBD administered alone showed a rapid but transient increase in neuronal activity in the MAM networks, an effect more pronounced in females. Furthermore, ILO had an additive effect on CBD-induced elevations in activity in the MAM male neurons. In the MAM female neurons, CBD or ILO administration resulted in time-dependent elevations in neuronal activity, but the short-term CBD-induced increases in activity were lost when CBD and ILO were combined. Our findings indicate that CBD induces rapid increases in cortical neuronal activity, with sex-specific drug interactions upon ILO coadministration. This suggests that sex should be a consideration when implementing adjunct therapy for treatment of SZ.

Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels

2019 ◽  
Author(s):  
Alessio Masi ◽  
Maria Novella Romanelli ◽  
Guido Mannaioni ◽  
Elisabetta Cerbai
Keyword(s):  
Cyclic Nucleotide ◽  
Hcn Channels ◽  
Neuronal Function ◽  
Excitable Cells ◽  
Cyclic Nucleotide Gated Channels ◽  
Pathological Conditions ◽  
Heart Muscle Cells ◽  
Neuronal Types ◽  
Close Relatives ◽  
Critical Aspects

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels are members of the voltage-gated K+ channels family, but with unique properties. In stark contrast to close relatives, HCN channels are permeable to both Na+ and K+, and they are activated by hyperpolarization. Activation by hyperpolarization is indeed a pretty funny feature, to the point that the physiologists who first characterized HCN current in heart muscle cells named it “funny current” or I f. Since then, the funny current has also been recorded from several neuronal types in both the central and peripheral nervous systems, as well as from some non-excitable cells, becoming progressively less “funny” over the years. In fact, HCN current goes now by the more serious designation of “I h,” for “hyperpolarization-activated.” Forty years after the first current recording, it is now established that HCN channels, by virtue of their special properties and a host of modulatory mechanisms, are profoundly involved in many critical aspects of neuronal function in physiological and pathological conditions.

scholarly journals Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 4005
Author(s):  
Giambattista Marotta ◽  
Filippo Basagni ◽  
Michela Rosini ◽  
Anna Minarini
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Symptomatic Relief ◽  
Acetylcholinesterase Inhibitors ◽  
Neurotransmitter System ◽  
Antioxidant Agents ◽  
Aβ Aggregation ◽  
Aggregation Inhibitors ◽  
Orally Active ◽  
Directed Structure

Memantine (3,5-dimethyladamantan-1-amine) is an orally active, noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist approved for treatment of moderate-to-severe Alzheimer’s disease (AD), a neurodegenerative condition characterized by a progressive cognitive decline. Unfortunately, memantine as well as the other class of drugs licensed for AD treatment acting as acetylcholinesterase inhibitors (AChEIs), provide only symptomatic relief. Thus, the urgent need in AD drug development is for disease-modifying therapies that may require approaching targets from more than one path at once or multiple targets simultaneously. Indeed, increasing evidence suggests that the modulation of a single neurotransmitter system represents a reductive approach to face the complexity of AD. Memantine is viewed as a privileged NMDAR-directed structure, and therefore, represents the driving motif in the design of a variety of multi-target directed ligands (MTDLs). In this review, we present selected examples of small molecules recently designed as MTDLs to contrast AD, by combining in a single entity the amantadine core of memantine with the pharmacophoric features of known neuroprotectants, such as antioxidant agents, AChEIs and Aβ-aggregation inhibitors.

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

2021 ◽  
Author(s):  
Viktor Szegedi ◽  
Emoke Bakos ◽  
Szabina Furdan ◽  
Pal Barzo ◽  
Gabor Tamas ◽  
...  
Keyword(s):  
Human Brain ◽  
Signal Transmission ◽  
Inhibitory Neurons ◽  
Basket Cell ◽  
Mammalian Brain ◽  
Resting Membrane Potential ◽  
Hcn Channels ◽  
Cyclic Nucleotide Gated Channels ◽  
Speed Up ◽  
Species Specific

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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