Chronic lithium treatment alters the excitatory/inhibitory balance of synaptic networks and reduces mGluR5-PKC signaling

Background: Bipolar disorder is characterized by cyclical alternation between mania and depression, often comorbid with psychosis and suicide. Compared with other medications, the mood stabilizer lithium is the most effective treatment for the prevention of manic and depressive episodes. However, the pathophysiology of bipolar disorder and lithium’s mode of action are yet to be fully understood. Evidence suggests a change in the balance of excitatory and inhibitory activity, favouring excitation in bipolar disorder. In the present study, we sought to establish a holistic understanding of the neuronal consequences of lithium exposure in mouse cortical neurons, and to identify underlying mechanisms of action. Methods: We used a range of technical approaches to determine the effects of acute and chronic lithium treatment on mature mouse cortical neurons. We combined RNA screening and biochemical and electrophysiological approaches with confocal immunofluorescence and live-cell calcium imaging. Results: We found that only chronic lithium treatment significantly reduced intracellular calcium flux, specifically by activating metabotropic glutamatergic receptor 5. This was associated with altered phosphorylation of protein kinase C and glycogen synthase kinase 3, reduced neuronal excitability and several alterations to synapse function. Consequently, lithium treatment shifts the excitatory–inhibitory balance toward inhibition. Limitations: The mechanisms we identified should be validated in future by similar experiments in whole animals and human neurons. Conclusion: Together, the results revealed how lithium dampens neuronal excitability and the activity of the glutamatergic network, both of which are predicted to be overactive in the manic phase of bipolar disorder. Our working model of lithium action enables the development of targeted strategies to restore the balance of overactive networks, mimicking the therapeutic benefits of lithium but with reduced toxicity.

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Elevated serotonergic signaling amplifies synaptic noise and facilitates the emergence of epileptiform network oscillations

Journal of Neurophysiology ◽

10.1152/jn.00031.2014 ◽

2014 ◽

Vol 112 (10) ◽

pp. 2357-2373 ◽

Cited By ~ 7

Author(s):

Pavel A. Puzerey ◽

Michael J. Decker ◽

Roberto F. Galán

Keyword(s):

Computational Model ◽

Cortical Neurons ◽

Neuronal Excitability ◽

Network Activity ◽

Cortical Dynamics ◽

Synaptic Excitation ◽

Network Oscillations ◽

Synaptic Noise ◽

Serotonin Signaling

Serotonin fibers densely innervate the cortical sheath to regulate neuronal excitability, but its role in shaping network dynamics remains undetermined. We show that serotonin provides an excitatory tone to cortical neurons in the form of spontaneous synaptic noise through 5-HT3 receptors, which is persistent and can be augmented using fluoxetine, a selective serotonin re-uptake inhibitor. Augmented serotonin signaling also increases cortical network activity by enhancing synaptic excitation through activation of 5-HT2 receptors. This in turn facilitates the emergence of epileptiform network oscillations (10–16 Hz) known as fast runs. A computational model of cortical dynamics demonstrates that these two combined mechanisms, increased background synaptic noise and enhanced synaptic excitation, are sufficient to replicate the emergence fast runs and their statistics. Consistent with these findings, we show that blocking 5-HT2 receptors in vivo significantly raises the threshold for convulsant-induced seizures.

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Altered network properties in C9ORF72 repeat expansion cortical neurons are due to synaptic dysfunction

Molecular Neurodegeneration ◽

10.1186/s13024-021-00433-8 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Emma M. Perkins ◽

Karen Burr ◽

Poulomi Banerjee ◽

Arpan R. Mehta ◽

Owen Dando ◽

...

Keyword(s):

Synaptic Plasticity ◽

Synaptic Vesicle ◽

Cortical Neurons ◽

Electrode Array ◽

Repeat Expansion ◽

Cortical Network ◽

Synaptic Function ◽

Network Activity ◽

Cortical Function ◽

Network Function

Abstract Background Physiological disturbances in cortical network excitability and plasticity are established and widespread in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those harbouring the C9ORF72 repeat expansion (C9ORF72RE) mutation – the most common genetic impairment causal to ALS and FTD. Noting that perturbations in cortical function are evidenced pre-symptomatically, and that the cortex is associated with widespread pathology, cortical dysfunction is thought to be an early driver of neurodegenerative disease progression. However, our understanding of how altered network function manifests at the cellular and molecular level is not clear. Methods To address this we have generated cortical neurons from patient-derived iPSCs harbouring C9ORF72RE mutations, as well as from their isogenic expansion-corrected controls. We have established a model of network activity in these neurons using multi-electrode array electrophysiology. We have then mechanistically examined the physiological processes underpinning network dysfunction using a combination of patch-clamp electrophysiology, immunocytochemistry, pharmacology and transcriptomic profiling. Results We find that C9ORF72RE causes elevated network burst activity, associated with enhanced synaptic input, yet lower burst duration, attributable to impaired pre-synaptic vesicle dynamics. We also show that the C9ORF72RE is associated with impaired synaptic plasticity. Moreover, RNA-seq analysis revealed dysregulated molecular pathways impacting on synaptic function. All molecular, cellular and network deficits are rescued by CRISPR/Cas9 correction of C9ORF72RE. Our study provides a mechanistic view of the early dysregulated processes that underpin cortical network dysfunction in ALS-FTD. Conclusion These findings suggest synaptic pathophysiology is widespread in ALS-FTD and has an early and fundamental role in driving altered network function that is thought to contribute to neurodegenerative processes in these patients. The overall importance is the identification of previously unidentified defects in pre and postsynaptic compartments affecting synaptic plasticity, synaptic vesicle stores, and network propagation, which directly impact upon cortical function.

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Treatment of Bipolar Disorder During the Postpartum Period

CNS Spectrums ◽

10.1017/s1092852900025724 ◽

2006 ◽

Vol 11 (S5) ◽

pp. 13-14

Author(s):

Adele C. Viguera

Keyword(s):

Bipolar Disorder ◽

Postpartum Period ◽

Clinical Information ◽

Mood Stabilizer ◽

Mood Stabilizers ◽

Antipsychotic Treatment ◽

Close Monitoring ◽

Major Congenital Malformations ◽

Major Depressive Episodes ◽

Depressive Episodes

AbstractThe presentations and clinical courses of patients with bipolar disorder differ greatly by gender. In addition, medical therapy must be tailored differently for men and women because of emerging safety concerns unique to the female reproductive system. In November 2005, these topics were explored by a panel of experts in psychiatry, neurology, and reproductive health at a closed roundtable meeting in Dallas, Texas. This clinical information monograph summarizes the highlights of that meeting.Compared to men with bipolar disorder, women have more pervasive depressive symptoms and experience more major depressive episodes. They are also at higher risk for obesity and certain other medical and psychiatric comorbidities. Mood changes across the menstrual cycle are common, although the severity, timing, and type of changes are variable. Bipolar disorder is frequently associated with menstrual abnormalities and ovarian dysfunction, including polycystic ovarian syndrome. Although some cases of menstrual disturbance precede the treatment of bipolar disorder, it is possible that valproate and/or antipsychotic treatment may play a contributory role in young women.Pregnancy does not protect against mood episodes in untreated women. Maintenance of euthymia during pregnancy is critical because relapse during this period strongly predicts a difficult postpartum course. Suspending therapy in the first months of pregnancy may be an option for some women with mild-to-moderate illness, or those with a long history of euthymia during pre-pregnancy treatment. However, a mood stabilizer should be reintroduced either in the later stages of pregnancy or in the immediate postpartum period. Preliminary data suggest that fetal exposure to some mood stabilizers may raise the risk of major congenital malformations and neurodevelopmental delays. For women planning to become pregnant, clinicians may consider switching to other drugs before conception. The value and drawbacks of breastfeeding during treatment must be considered in partnership with the patient, with close monitoring of nursing infants thereafter. The risks and benefits of medical treatment for women with bipolar disorder should be carefully reconsidered at each stage of their reproductive lives, with a flexible approach that is responsive to the changing needs of patients and their families.

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Aldolase C/Zebrin II is Released to the Extracellular Space after Stroke and Inhibits the Network Activity of Cortical Neurons

Neurochemical Research ◽

10.1007/s11064-006-9169-9 ◽

2006 ◽

Vol 31 (11) ◽

pp. 1297-1303 ◽

Cited By ~ 10

Author(s):

Stephanie Linke ◽

Philipp Goertz ◽

Stephan L. Baader ◽

Volkmar Gieselmann ◽

Mario Siebler ◽

...

Keyword(s):

Cortical Neurons ◽

Extracellular Space ◽

Network Activity ◽

Aldolase C ◽

Zebrin Ii

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Mining the Virgin Land of Neurotoxicology: A Novel Paradigm of Neurotoxic Peptides Action on Glycosylated Voltage-Gated Sodium Channels

Journal of Toxicology ◽

10.1155/2012/843787 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 3

Author(s):

Zhirui Liu ◽

Jie Tao ◽

Pin Ye ◽

Yonghua Ji

Keyword(s):

Sodium Channels ◽

Network Activity ◽

Voltage Gated ◽

Virgin Land ◽

Neuronal Network Activity ◽

Voltage Gated Sodium Channels ◽

Pharmacological Targets ◽

Underlying Mechanisms ◽

Posttranslation Modification

Voltage-gated sodium channels (VGSCs) are important membrane protein carrying on the molecular basis for action potentials (AP) in neuronal firings. Even though the structure-function studies were the most pursued spots, the posttranslation modification processes, such as glycosylation, phosphorylation, and alternative splicing associating with channel functions captured less eyesights. The accumulative research suggested an interaction between the sialic acids chains and ion-permeable pores, giving rise to subtle but significant impacts on channel gating. Sodium channel-specific neurotoxic toxins, a family of long-chain polypeptides originated from venomous animals, are found to potentially share the binding sites adjacent to glycosylated region on VGSCs. Thus, an interaction between toxin and glycosylated VGSC might hopefully join the campaign to approach the role of glycosylation in modulating VGSCs-involved neuronal network activity. This paper will cover the state-of-the-art advances of researches on glycosylation-mediated VGSCs function and the possible underlying mechanisms of interactions between toxin and glycosylated VGSCs, which may therefore, fulfill the knowledge in identifying the pharmacological targets and therapeutic values of VGSCs.

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Acute Stimulation of Dissociated Cortical Neurons of Newborn Rats with Orexin A: Effect on the Network Activity

IFMBE Proceedings - 8th International Conference on Cell & Stem Cell Engineering (ICCE) ◽

10.1007/978-3-642-19044-5_10 ◽

2011 ◽

pp. 35-38 ◽

Cited By ~ 1

Author(s):

I. I. Stoyanova ◽

J. Feber ◽

W. L. C. Rutten

Keyword(s):

Cortical Neurons ◽

Network Activity ◽

Newborn Rats ◽

Orexin A ◽

Dissociated Cortical Neurons ◽

Stimulation Of

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Effects of In Utero Exposure to AEDs on Morphology and Neurodevelopment

CNS Spectrums ◽

10.1017/s1092852900025700 ◽

2006 ◽

Vol 11 (S5) ◽

pp. 9-10

Author(s):

Martha J. Morrell

Keyword(s):

Bipolar Disorder ◽

Clinical Information ◽

Mood Stabilizer ◽

Mood Stabilizers ◽

Antipsychotic Treatment ◽

Close Monitoring ◽

History Of ◽

Major Congenital Malformations ◽

Major Depressive Episodes ◽

Depressive Episodes

AbstractThe presentations and clinical courses of patients with bipolar disorder differ greatly by gender. In addition, medical therapy must be tailored differently for men and women because of emerging safety concerns unique to the female reproductive system. In November 2005, these topics were explored by a panel of experts in psychiatry, neurology, and reproductive health at a closed roundtable meeting in Dallas, Texas. This clinical information monograph summarizes the highlights of that meeting.Compared to men with bipolar disorder, women have more pervasive depressive symptoms and experience more major depressive episodes. They are also at higher risk for obesity and certain other medical and psychiatric comorbidities. Mood changes across the menstrual cycle are common, although the severity, timing, and type of changes are variable. Bipolar disorder is frequently associated with menstrual abnormalities and ovarian dysfunction, including polycystic ovarian syndrome. Although some cases of menstrual disturbance precede the treatment of bipolar disorder, it is possible that valproate and/or antipsychotic treatment may play a contributory role in young women.Pregnancy does not protect against mood episodes in untreated women. Maintenance of euthymia during pregnancy is critical because relapse during this period strongly predicts a difficult postpartum course. Suspending therapy in the first months of pregnancy may be an option for some women with mild-to-moderate illness, or those with a long history of euthymia during pre-pregnancy treatment. However, a mood stabilizer should be reintroduced either in the later stages of pregnancy or in the immediate postpartum period. Preliminary data suggest that fetal exposure to some mood stabilizers may raise the risk of major congenital malformations and neurodevelopmental delays. For women planning to become pregnant, clinicians may consider switching to other drugs before conception. The value and drawbacks of breastfeeding during treatment must be considered in partnership with the patient, with close monitoring of nursing infants thereafter. The risks and benefits of medical treatment for women with bipolar disorder should be carefully reconsidered at each stage of their reproductive lives, with a flexible approach that is responsive to the changing needs of patients and their families.

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Neuritin Up-regulates Kv4.2 α-Subunit of Potassium Channel Expression and Affects Neuronal Excitability by Regulating the Calcium-Calcineurin-NFATc4 Signaling Pathway

Journal of Biological Chemistry ◽

10.1074/jbc.m115.708883 ◽

2016 ◽

Vol 291 (33) ◽

pp. 17369-17381 ◽

Cited By ~ 19

Author(s):

Jin-jing Yao ◽

Qian-Ru Zhao ◽

Dong-Dong Liu ◽

Chi-Wing Chow ◽

Yan-Ai Mei

Keyword(s):

Signaling Pathway ◽

Neural Development ◽

Cortical Neurons ◽

Molecular Mechanisms ◽

Neuronal Excitability ◽

Outward Current ◽

Nuclear Accumulation ◽

Luciferase Reporter ◽

Activated T Cells ◽

Α Subunit

Neuritin is an important neurotrophin that regulates neural development, synaptic plasticity, and neuronal survival. Elucidating the downstream molecular signaling is important for potential therapeutic applications of neuritin in neuronal dysfunctions. We previously showed that neuritin up-regulates transient potassium outward current (IA) subunit Kv4.2 expression and increases IA densities, in part by activating the insulin receptor signaling pathway. Molecular mechanisms of neuritin-induced Kv4.2 expression remain elusive. Here, we report that the Ca2+/calcineurin (CaN)/nuclear factor of activated T-cells (NFAT) c4 axis is required for neuritin-induced Kv4.2 transcriptional expression and potentiation of IA densities in cerebellum granule neurons. We found that neuritin elevates intracellular Ca2+ and increases Kv4.2 expression and IA densities; this effect was sensitive to CaN inhibition and was eliminated in Nfatc4−/− mice but not in Nfatc2−/− mice. Stimulation with neuritin significantly increased nuclear accumulation of NFATc4 in cerebellum granule cells and HeLa cells, which expressed IR. Furthermore, NFATc4 was recruited to the Kv4.2 gene promoter loci detected by luciferase reporter and chromatin immunoprecipitation assays. More importantly, data obtained from cortical neurons following adeno-associated virus-mediated overexpression of neuritin indicated that reduced neuronal excitability and increased formation of dendritic spines were abrogated in the Nfatc4−/− mice. Together, these data demonstrate an indispensable role for the CaN/NFATc4 signaling pathway in neuritin-regulated neuronal functions.

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Spontaneous dynamics of neural networks in deep layers of prefrontal cortex

Journal of Neurophysiology ◽

10.1152/jn.00295.2016 ◽

2017 ◽

Vol 117 (4) ◽

pp. 1581-1594 ◽

Cited By ~ 4

Author(s):

Andrew S. Blaeser ◽

Barry W. Connors ◽

Arto V. Nurmikko

Keyword(s):

Prefrontal Cortex ◽

Spontaneous Activity ◽

Calcium Imaging ◽

Cortical Neurons ◽

Rhythmic Activity ◽

Network Activity ◽

Local Networks ◽

Spatiotemporal Scale ◽

Deep Layers ◽

Delta Oscillations

Cortical systems maintain and process information through the sustained activation of recurrent local networks of neurons. Layer 5 is known to have a major role in generating the recurrent activation associated with these functions, but relatively little is known about its intrinsic dynamics at the mesoscopic level of large numbers of neighboring neurons. Using calcium imaging, we measured the spontaneous activity of networks of deep-layer medial prefrontal cortical neurons in an acute slice model. Inferring the simultaneous activity of tens of neighboring neurons, we found that while the majority showed only sporadic activity, a subset of neurons engaged in sustained delta frequency rhythmic activity. Spontaneous activity under baseline conditions was weakly correlated between pairs of neurons, and rhythmic neurons showed little coherence in their oscillations. However, we consistently observed brief bouts of highly synchronous activity that must be attributed to network activity. NMDA-mediated stimulation enhanced rhythmicity, synchrony, and correlation within these local networks. These results characterize spontaneous prefrontal activity at a previously unexplored spatiotemporal scale and suggest that medial prefrontal cortex can act as an intrinsic generator of delta oscillations. NEW & NOTEWORTHY Using calcium imaging and a novel analytic framework, we characterized the spontaneous and NMDA-evoked activity of layer 5 prefrontal cortex at a largely unexplored spatiotemporal scale. Our results suggest that the mPFC microcircuitry is capable of intrinsically generating delta oscillations and sustaining synchronized network activity that is potentially relevant for understanding its contribution to cognitive processes.

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