Mechanisms Underlying the Hyperexcitability of CA3 and Dentate Gyrus Hippocampal Neurons Derived From Patients With Bipolar Disorder

Stern, Shani; Sarkar, Anindita; Stern, Tchelet; Mei, Arianna; Mendes, Ana Cristina; Stern, Yam; Goldberg, Gabriela; Galor, Dekel; Nguyen, Thao H.; Randolph‐Moore, Lynne; Kim, Yongsung; Rouleau, Guy A.; Bang, Anne G.; Alda, Martin; Santos, Renata; Marchetto, Maria C.; Gage, Fred H.

doi:10.1016/j.biopsych.2019.09.018

Cited by 55 publications

(71 citation statements)

References 52 publications

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“…Our first two studies in this line of research described in detail the phenotype that DG neurons derived from BD patients exhibited: hyperexcitability in the form of sustained activity. Our most recent study (3) describes the phenotype of another type of hippocampal neuron, the CA3 pyramidal neuron, and further unravels a mechanism that is responsible for the measured phenotypes.…”

Section: Introductionmentioning

confidence: 90%

“…For a DG neuron, a published (20) cell morphology was used. Another type of ion channel was added to the model to represent the fast kinetics potassium channel Kv3.1 (21) to both DG and CA3 simulations, due to the altered expression of these channels (3).…”

Section: Simulationmentioning

confidence: 99%

“…We have shown the involvement of potassium currents in the hyperexcitability phenotype in BD (3). We next used the changes that we measured in the currents respectively as changes to channel conductances in a numerical model for BD.…”

Section: A Computational Model For a Bd Dg Granule Neuron And A Ca3 Pmentioning

confidence: 99%

“…Bipolar disorder (BD) is a devastating neuropsychiatric disease affecting 1-3% of the general population, causing a major economic burden and drastically reducing the quality of life of patients. Induced pluripotent stem cell (iPSC) technology has allowed us to study BD in neurons derived from human patients (3)(4)(5).This approach was an exciting advance because it allowed viable cell studies in a disease for which animal models did not fully reconstruct the complicated genetics. Neither did these models fully recapitulate the symptoms of human patients (6,7).…”

Section: Introductionmentioning

confidence: 99%

“…In this study we used our experimental data presented in (3,5) to build a numerical simulation of the two types of studied hippocampal neurons: DG and CA3 pyramidal neurons. By increasing the conductance of a few types of the fast potassium currents and the sodium current, we were able to simulate BD LR and BD NR neurons for both DG and CA3 pyramidal neurons with the experimental phenotypes.…”

Section: Introductionmentioning

confidence: 99%

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A Physiological Instability Displayed in Hippocampal Neurons Derived From Lithium-Nonresponsive Bipolar Disorder Patients

Stern

Sarkar

Galor

et al. 2020

Biological Psychiatry

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Background: We recently reported a hyperexcitability phenotype displayed in dentate gyrus (DG) granule neurons derived from bipolar disorder (BD) patients (1, 2) and also a hyperexcitability that appeared only in CA3 pyramidal hippocampal neurons that were derived from BD patients who responded to lithium treatment (LR) but not from BD patients who were lithium non-responders (NR) (3). Methods: Here we used our measurements of currents in neurons derived from 4 control individuals, 3 LR BD patients, and 3 NR BD patients. We have changed the conductances of simulated DG and CA3 hippocampal neurons according our measurements to derive a numerical simulation for BD neurons. Results: The computationally simulated BD DG neurons had a hyperexcitability phenotype similar to the experimental results. The simulated BD CA3 neurons were only hyperexcitable when derived from LR BD patients. Interestingly, our computational model captured a physiological instability intrinsic to hippocampal neurons that were derived from NR BD patients that we also observed when reexamining our experimental results. This instability is caused by a drastic reduction in the sodium current, accompanied by an increase in the amplitude of the fast potassium currents. These baseline alterations cause NR 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 BD patients.

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Section: Introductionmentioning

confidence: 90%

Section: Simulationmentioning

confidence: 99%

Section: A Computational Model For a Bd Dg Granule Neuron And A Ca3 Pmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Physiological Instability Displayed in Hippocampal Neurons Derived From Lithium-Nonresponsive Bipolar Disorder Patients

Stern

Sarkar

Galor

et al. 2020

Biological Psychiatry

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Lithium use associated with symptom severity in comorbid bipolar disorder I and migraine

et al. 2022

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Introduction: Bipolar disorder (BD) and migraine headaches are frequently comorbid. The common etiological features are unknown, however cortical hyperexcitability (EEG) of migraines, and the report of hyperexcitability in pluripotent stem cellderived neurons from lithium responsive BD subjects offers a physiological hypothesis of excitable neurons linking these disorders. However, clinical studies suggest that a history of migraine is associated with higher rates of relapse in those with BD taking lithium. Lithium use and history of migraine in this prospective longitudinal study of BD find that lithium use is associated with a greater symptom severity in BD.Methods: Data on longitudinal outcome from 538 patients with BD I were categorized according to treatment with lithium and comorbidity with migraine. Clinical outcome measures on depression, mania, and quality of life over the most recent 2-year period compared the BD and BD/migraine cohort according to lithium treatment status.Results: A history of migraines was associated with worse clinical outcomes of depression (p = .002), mania (p = .005), and mental and physical quality of life (p = .004 and p = .005, respectively), independent of lithium use. The BD/migraine cohort treated with lithium was associated with worse symptoms of mania, whereas those without migraine and lithium use were associated with milder manic symptoms (p = .026).Conclusions: Herein, we replicate the relatively worse outcome in BD with comorbid migraine. We find evidence to suggest that lithium use is associated with more severe symptoms of mania among those with BD and a history of migraine and conclude that lithium is contraindicated in BD comorbid with migraine.

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NMDA receptor activity during postnatal development determines intrinsic excitability and mossy fiber long‐term potentiation of CA3 pyramidal cells

et al. 2023

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Experimental manipulations that interfere with the functional expression of N‐methyl‐D‐aspartate receptors (NMDARs) during prenatal neurodevelopment or critical periods of postnatal development are models that mimic behavioral and neurophysiological abnormalities of schizophrenia. Blockade of NMDARs with MK‐801 during early postnatal development alters glutamate release and impairs the induction of NMDAR‐dependent long‐term plasticity at the CA1 area of the hippocampus. However, it remains unknown if other forms of hippocampal plasticity, such as α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR)‐mediated short‐ and long‐term potentiation, are compromised in response to neonatal treatment with MK‐801. Consistent with this tenet, short‐ and long‐term potentiation between dentate gyrus axons, the mossy fibers (MF), onto CA3 pyramidal cells (CA3 PCs) are mediated by AMPARs. By combining whole‐cell patch clamp and extracellular recordings, we have demonstrated that transient blockade of NMDARs during early postnatal development induces a series of pre‐ and postsynaptic modifications at the MF—CA3 synapse. We found reduced glutamate release from the mossy boutons, increased paired‐pulse ratio, and reduced AMPAR‐mediated MF LTP levels. At the postsynaptic level, we found an altered NMDA/AMPA ratio and dysregulation of several potassium conductances that increased the excitability of CA3 PCs. In addition, MK‐801‐treated animals exhibited impaired spatial memory retrieval in the Barnes maze task. Our data demonstrate that transient hypofunction of NMDARs impacts NMDAR‐independent forms of synaptic plasticity of the hippocampus.

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Mechanisms Underlying the Hyperexcitability of CA3 and Dentate Gyrus Hippocampal Neurons Derived From Patients With Bipolar Disorder

Cited by 55 publications

References 52 publications

A Physiological Instability Displayed in Hippocampal Neurons Derived From Lithium-Nonresponsive Bipolar Disorder Patients

A Physiological Instability Displayed in Hippocampal Neurons Derived From Lithium-Nonresponsive Bipolar Disorder Patients

Lithium use associated with symptom severity in comorbid bipolar disorder I and migraine

NMDA receptor activity during postnatal development determines intrinsic excitability and mossy fiber long‐term potentiation of CA3 pyramidal cells

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