| | Models | Description |
| 1. |
A model of ventral Hippocampal CA1 pyramidal neurons of Tg2576 AD mice (Spoleti et al. 2021)
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Gradual decline in cognitive and non-cognitive functions are considered clinical hallmarks of Alzheimer's Disease (AD). Post-mortem autoptic analysis shows the presence of amyloid ß deposits, neuroinflammation and severe brain atrophy. However, brain circuit alterations and cellular derailments, assessed in very early stages of AD, still remain elusive. The understanding of these early alterations is crucial to tackle defective mechanisms.
In a previous study we proved that the Tg2576 mouse model of AD displays functional deficits in the dorsal hippocampus and relevant behavioural AD-related alterations. We had shown that these deficits in Tg2576 mice correlate with the precocious degeneration of dopamine (DA) neurons in the Ventral Tegmental Area (VTA) and can be restored by L-DOPA treatment. Due to the distinct functionality and connectivity of dorsal versus ventral hippocampus, here we investigated neuronal excitability and synaptic functionality in the ventral CA1 hippocampal sub-region of Tg2576 mice. We found an age-dependent alteration of cell excitability and firing in pyramidal neurons starting at 3 months of age, that correlates with reduced levels in the ventral CA1 of tyrosine hydroxylase – the rate-limiting enzyme of DA synthesis. Additionally, at odds with the dorsal hippocampus, we found no alterations in basal glutamatergic transmission and long-term plasticity of ventral neurons in 8-month old Tg2576 mice compared to age-matched controls. Last, we used computational analysis to model the early derailments of firing properties observed and hypothesize that the neuronal alterations found could depend on dysfunctional sodium and potassium conductances, leading to anticipated depolarization-block of action potential firing. The present study depicts that impairment of cell excitability and homeostatic control of firing in ventral CA1 pyramidal neurons is a prodromal feature in Tg2576 AD mice.
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| 2. |
A Neural mass computational model of the Thalamocorticothalamic circuitry (Bhattacharya et al. 2011)
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The model presented here is a bio-physically plausible version of a simple thalamo-cortical neural mass computational model proposed by Lopes da Silva in 1974 to simulate brain EEG activity within the alpha band (8-13 Hz). The thalamic and cortical circuitry are presented as separate modules in this model with cell populations as in biology. The connectivity between cell populations are as reported by Sherman, S. in Scholarpedia, 2006. The values of the synaptic connectivity parameters are as reported by Van Horn et al, 2000. In our paper (doi:10.1016/j.neunet.2011.02.009), we study the model behaviour while varying the values of the synaptic connectivity parameters (Cyyy) in the model about their respective 'basal' (intial) values. |
| 3. |
Age-dependent excitability of CA1 pyramidal neurons in APPPS1 Alzheimer's model (Vitale et al 2021)
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Age-dependent accumulation of amyloid-b, provoking increasing brain amyloidopathy, triggers abnormal patterns of neuron activity and circuit synchronization in Alzheimer’s disease (AD) as observed in human AD patients and AD mouse models. Recent studies on AD mouse models, mimicking this age-dependent amyloidopathy, identified alterations in CA1 neuron excitability. However, these models generally also overexpress mutated amyloid precursor protein (APP) and presenilin 1 (PS1) and there is a lack of a clear correlation of neuronal excitability alterations with progressive amyloidopathy. The active development of computational models of AD points out the need of collecting such experimental data to build a reliable disease model exhibiting AD-like disease progression. We therefore used the feature extraction tool of the Human Brain Project (HBP) Brain Simulation Platform to systematically analyze the excitability profile of CA1 pyramidal neuron in the APPPS1 mouse model. We identified specific features of neuron excitability that best correlate either with over-expression of mutated APP and PS1 or increasing Ab amyloidopathy. Notably, we report strong alterations in membrane time constant and action potential width and weak alterations in firing behavior. Also, using a CA1 pyramidal neuron model, we evidence amyloidopathy-dependent alterations in Ih. Finally, cluster analysis of these recordings showed that we could reliably assign a trace to its correct group, opening the door to a more refined, less variable analysis of AD-affected neurons. This inter-disciplinary analysis, bringing together experimentalists and modelers, helps to further unravel the neuronal mechanisms most affected by AD and to build a biologically plausible computational model of the AD brain.
Reference: Paola Vitale, Ana Rita Salgueiro-Pereira, Carmen Alina Lupascu, Rosanna Migliore, Michele Migliore, Hélène Marie. "Analysis of age-dependent alterations in excitability properties of CA1 pyramidal neurons in an APPPS1 model of Alzheimer's disease". Frontiers in Aging Neuroscience (2021) DOI: 10.3389/fnagi.2021.668948 |
| 4. |
Amyloid beta (IA block) effects on a model CA1 pyramidal cell (Morse et al. 2010)
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The model simulations provide evidence oblique dendrites in CA1 pyramidal neurons are susceptible to hyper-excitability by amyloid beta block of the transient K+ channel, IA. See paper for details. |
| 5. |
Amyloid-beta effects on release probability and integration at CA3-CA1 synapses (Romani et al. 2013)
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The role of amyloid beta (Aß) in brain function and in the pathogenesis of Alzheimer’s disease remains elusive.
Recent publications reported that an increase in Aß concentration perturbs presynaptic release in hippocampal neurons, in particular by increasing release probability of CA3-CA1 synapses. The model predics how this alteration can affect synaptic plasticity and signal integration. The results suggest that the perturbation of release probability induced by increased Aß can significantly alter the spike probability of CA1 pyramidal neurons and thus contribute to abnormal hippocampal function during Alzheimer’s disease. |
| 6. |
Axonal spheroids and conduction defects in Alzheimer’s disease (Yuan, Zhang, Tong, et al 2022)
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PAAS (plaque-associated axonal spheroid(s)) are dystrophic structures that sprout from axons that pass through amyloid beta plaques. If small enough they do not interfere with action potential (AP) propagation. Medium sized ones delay APs, and large, or many spheroids can block single APs and block or delay trains of APs. |
| 7. |
CA1 pyramidal neurons: effects of Alzheimer (Culmone and Migliore 2012)
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The model predicts possible therapeutic treatments of Alzheimers's Disease in terms of pharmacological manipulations of channels' kinetic and activation properties. The results suggest how and which mechanism can be targeted by a drug to restore the original firing conditions. The simulations reproduce somatic membrane potential in control conditions, when 90% of membrane is affected by AD (Fig.4A of the paper), and after treatment (Fig.4B of the paper).
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| 8. |
Computational neuropharmacology of CA1 pyramidal neuron (Ferrante et al. 2008)
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In this paper, the model was used to show how neuroactive drugs targeting different neuronal mechanisms affect the signal integration in CA1 pyramidal neuron. Ferrante M, Blackwell KT, Migliore M, Ascoli GA (2008) |
| 9. |
Effects of increasing CREB on storage and recall processes in a CA1 network (Bianchi et al. 2014)
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Several recent results suggest that boosting the CREB pathway improves hippocampal-dependent memory in healthy rodents and restores this type of
memory in an AD mouse model. However, not much is known about how CREB-dependent neuronal alterations in synaptic strength, excitability and
LTP can boost memory formation in the complex architecture of a neuronal network. Using a model of a CA1 microcircuit, we investigate whether
hippocampal CA1 pyramidal neuron properties altered by increasing CREB activity may contribute to improve memory storage and recall. With a set of patterns presented to a network, we find that the pattern recall quality under AD-like conditions is significantly better when boosting CREB function with respect to control. The results are robust and consistent upon increasing the synaptic damage expected by AD progression, supporting the idea that the use of CREB-based therapies could provide a new approach
to treat AD. |
| 10. |
Electrostimulation to reduce synaptic scaling driven progression of Alzheimers (Rowan et al. 2014)
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"...
As cells die and synapses lose their drive, remaining cells suffer an initial decrease in activity.
Neuronal homeostatic synaptic scaling then provides a feedback mechanism to restore activity.
...
The scaling mechanism increases the firing rates of remaining cells in the network to compensate for decreases in network activity.
However, this effect can itself become a pathology, ...
Here, we present a mechanistic explanation of how directed brain stimulation might be expected to slow AD progression based on computational simulations in a 470-neuron biomimetic model of a neocortical column.
...
" |
| 11. |
Human L5 Cortical Circuit (Guet-McCreight)
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We used L5 Pyr neuron models fit to electrophysiology data from younger and older individuals to simulate detailed human layer 5 microcircuits. These circuits also included detailed parvalbumin+ (PV), somatostatin+ (SST), and vasoactivate intestinal polypeptide+ (VIP) inhibitory interneuron models. |
| 12. |
Modelling reduced excitability in aged CA1 neurons as a Ca-dependent process (Markaki et al. 2005)
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"We use a multi-compartmental model of a CA1 pyramidal cell to study changes in hippocampal excitability that result from aging-induced alterations in calcium-dependent membrane mechanisms.
The model incorporates N- and L-type calcium channels which are respectively coupled to fast and slow afterhyperpolarization potassium channels.
Model parameters are calibrated using physiological data.
Computer simulations reproduce the decreased excitability of aged CA1 cells, which results from increased internal calcium accumulation, subsequently larger postburst slow afterhyperpolarization, and enhanced spike frequency adaptation.
We find that aging-induced alterations in CA1 excitability can be modelled with simple coupling mechanisms that selectively link specific types of calcium channels to specific calcium-dependent potassium channels." |
| 13. |
Rhesus Monkey Layer 3 Pyramidal Neurons: Young vs aged PFC (Coskren et al. 2015)
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Layer 3 (L3) pyramidal neurons in the lateral prefrontal cortex (LPFC) of rhesus monkeys exhibit dendritic regression, spine loss and increased action potential (AP) firing rates during normal aging. The relationship between these structural and functional alterations, if any, is unknown. Computational models using the digital reconstructions with Hodgkin-Huxley and AMPA channels allowed us to assess relationships between demonstrated age-related changes and to predict physiological changes that have not yet been tested empirically. Tuning passive parameters for each model predicted significantly higher membrane resistance (Rm) in aged versus young neurons. This Rm increase alone did not account for the empirically observed fI-curves, but coupling these Rm values with subtle differences in morphology and membrane capacitance Cm did. The predicted differences in passive parameters (or other parameters with similar effects) are mathematically plausible, but
must be tested empirically. |
| 14. |
Rhesus Monkey Young and Aged L3 PFC Pyramidal Neurons (Rumbell et al. 2016)
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A stereotypical pyramidal neuron morphology with ion channel parameter combinations that reproduce firing patterns of one young and one aged rhesus monkey L3 PFC pyramidal neurons. Parameters were found through an automated optimization method. |
| 15. |
The APP in C-terminal domain alters CA1 neuron firing (Pousinha et al 2019)
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"The amyloid precursor protein (APP) is central to AD pathogenesis and we recently showed that its intracellular domain (AICD) could modify synaptic signal integration. We now hypothezise that AICD modifies neuron firing activity, thus contributing to the disruption of memory processes. Using cellular, electrophysiological and behavioural techniques, we showed that pathological AICD levels weakens CA1 neuron firing activity through a gene transcription-dependent mechanism. Furthermore, increased AICD production in hippocampal neurons modifies oscillatory activity, specifically in the gamma frequency range, and disrupts spatial memory task. Collectively, our data suggest that AICD pathological levels, observed in AD mouse models and in human patients, might contribute to progressive neuron homeostatic failure, driving the shift from normal ageing to AD." |
| 16. |
Tonic activation of extrasynaptic NMDA-R promotes bistability (Gall & Dupont 2020)
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Our theoretical model provides a simple description of neuronal electrical activity that takes into account the tonic activity of extrasynaptic NMDA receptors and a cytosolic calcium compartment. We show that calcium influx mediated by the tonic activity of NMDA-R can be coupled directly to the activation of calcium-activated potassium channels, resulting in an overall inhibitory effect on neuronal excitability. Furthermore, the presence of tonic NMDA-R activity promotes bistability in electrical activity by dramatically increasing the stimulus interval where both a stable steady state and repetitive firing can coexist. These results could provide an intrinsic mechanism for the constitution of memory traces in neuronal circuits. |
