Abstract
Background
We recently reported a hyperexcitability phenotype displayed in dentate gyrus granule
neurons derived from patients with bipolar disorder (BD) as well as a hyperexcitability
that appeared only in CA3 pyramidal hippocampal neurons that were derived from patients
with BD who responded to lithium treatment (lithium responders) and not in CA3 pyramidal
hippocampal neurons that were derived from patients with BD who did not respond to
lithium (nonresponders).
Methods
Here we used our measurements of currents in neurons derived from 4 control subjects,
3 patients with BD who were lithium responders, and 3 patients with BD who were nonresponders.
We changed the conductances of simulated dentate gyrus and CA3 hippocampal neurons
according to our measurements to derive a numerical simulation for BD neurons.
Results
The computationally simulated BD dentate gyrus neurons had a hyperexcitability phenotype
similar to the experimental results. Only the simulated BD CA3 neurons derived from
lithium responder patients were hyperexcitable. Interestingly, our computational model
captured a physiological instability intrinsic to hippocampal neurons that were derived
from nonresponder patients that we also observed when re-examining our experimental
results. This instability was caused by a drastic reduction in the sodium current,
accompanied by an increase in the amplitude of several potassium currents. These baseline
alterations caused nonresponder BD hippocampal neurons to drastically shift their
excitability with small changes to their sodium currents, alternating between hyperexcitable
and hypoexcitable states.
Conclusions
Our computational model of BD hippocampal neurons that was based on our measurements
reproduced the experimental phenotypes of hyperexcitability and physiological instability.
We hypothesize that the physiological instability phenotype strongly contributes to
affective lability in patients with BD.
Keywords
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References
- Mechanisms underlying the hyperexcitability of CA3 and dentate gyrus hippocampal neurons derived from patients with bipolar disorder.Biol Psychiatry. 2020; : 139-149
- Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder.Nature. 2015; 527: 95-99
- Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients’ responsiveness to lithium.Mol Psychiatry. 2018; 23: 1453-1465
- Animal models for bipolar disorder: From bedside to the cage.Int J Bipolar Disord. 2017; 5: 35
- Animal models of neuropsychiatric disorders.Nat Neurosci. 2010; 13: 1161-1169
- Prediction of response to drug therapy in psychiatric disorders.Open Biol. 2018; 8: 180031
- Predictors of lithium response in bipolar disorder.Ther Adv Chronic Dis. 2011; 2: 209-226
- Treatment of mixed bipolar states.Int J Neuropsychopharmacol. 2012; 15: 1015-1026
- Clinical factors associated with lithium response in bipolar disorders.Aust N Z J Psychiatry. 2017; 51: 524-530
- Childhood trauma and mixed episodes are associated with poor response to lithium in bipolar disorders.Acta Psychiatr Scand. 2017; 135: 319-327
- Pharmacotherapy of bipolar mixed states.Bipolar Disord. 2005; 7: 205-215
- Identifying predictors for good lithium response—a retrospective analysis of 100 patients with bipolar disorder using a life-charting method.Eur Psychiatry. 2009; 24: 171-177
- Modeling hippocampal neurogenesis using human pluripotent stem cells.Stem Cell Rep. 2014; 2: 295-310
- Efficient generation of CA3 neurons from human pluripotent stem cells enables modeling of hippocampal connectivity in vitro.Cell Stem Cell. 2018; 22: 684-697.e689
- Involvement of potassium and cation channels in hippocampal abnormalities of embryonic Ts65Dn and Tc1 trisomic mice.EBioMedicine. 2015; 2: 1048-1062
- The NEURON simulation environment.Neural Comput. 1997; 9: 1179-1209
- Computer simulations of morphologically reconstructed CA3 hippocampal neurons.J Neurophysiol. 1995; 73: 1157-1168
- Role of multiple calcium and calcium-dependent conductances in regulation of hippocampal dentate granule cell excitability.J Comput Neurosci. 1999; 6: 215-235
- Contribution of the Kv3.1 potassium channel to high-frequency firing in mouse auditory neurones.J Physiol. 1998; 509: 183-194
- Transcripts involved in calcium signaling and telencephalic neuronal fate are altered in induced pluripotent stem cells from bipolar disorder patients.Transl Psychiatry. 2014; 4: e375
- Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder.Nat Genet. 2008; 40: 1056-1058
- A new bursting model of CA3 pyramidal cell physiology suggests multiple locations for spike initiation.Biosystems. 2002; 67: 129-137
- Estimating use-dependent synaptic gain in autonomic ganglia by computational simulation and dynamic-clamp analysis.J Neurophysiol. 2004; 92: 2659-2671
- Abnormal excitability of oblique dendrites implicated in early Alzheimer’s: A computational study.Front Neural Circuits. 2010; 4: 16
- Global structure, robustness, and modulation of neuronal models.J Neurosci. 2001; 21: 5229-5238
Article info
Publication history
Published online: February 04, 2020
Accepted:
January 24,
2020
Received in revised form:
January 8,
2020
Received:
April 18,
2019
Identification
Copyright
© 2020 Society of Biological Psychiatry.
ScienceDirect
Access this article on ScienceDirectLinked Article
- Can Computational Modeling Predict Disease Phenotype?Biological PsychiatryVol. 88Issue 2
- PreviewTo understand the cellular and molecular pathophysiology of mood disorders, including bipolar disorder (BD), has been an inherently challenging task. One of the primary barriers is the infeasibility of accessing live neuronal cells and tissue from patients to undertake experiments in the laboratory. Even though postmortem studies provide a great depth of knowledge, they cannot demonstrate precisely when during the neurodevelopmental trajectory the disease develops.
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