The role of norepinephrine in the pathophysiology of schizophrenia

Mäki-Marttunen, Verónica; Andreassen, Ole A.; Espeseth, Thomas

doi:10.31219/osf.io/xc8qu

Cited by 10 publications

(7 citation statements)

References 258 publications

(320 reference statements)

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“…Finally, in Section 3.4, we used a multicompartmental model of a layer 2/3 pyramidal cell [Markram et al, 2015] (L23 PC cADpyr229 5) to determine the amplitudes and time courses of the Ca 2+ inputs conducted by NMDA receptors (NMDARs) when different pairing intervals were applied. We used the probabilistic AMPA-NMDA synapse model of [Hay and Segev, 2015] with the NMDA gating mechanism of [Spruston et al, 1995], a correction in the pre-synaptic resource update [Mäki-Marttunen et al, 2018] and an AMPA-NMDA ratio of 1:7. We estimated the numbers of Ca 2+ ions entering into post-synaptic spines consisting of a 0.5 µm long and 0.1 µm thick neck and a 0.4 µm long and 0.4 µm thick head across time, and used these numbers as the input to the biochemical model.…”

Section: Modelling the Ca 2+ Inputs And Neuromodulatory Inputsmentioning

confidence: 99%

A unified computational model for cortical post-synaptic plasticity

Mäki‐Marttunen

Iannella

Edwards

et al. 2020

Preprint

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Cortical synapses possess a machinery of signalling pathways that leads to various modes of post-synaptic plasticity. Such pathways have been examined to a great detail separately in many types of experimental studies. However, a unified picture on how multiple biochemical pathways collectively shape the observed synaptic plasticity in the neocortex is missing. Here, we built a biochemically detailed model of post-synaptic plasticity that includes the major signalling cascades, namely, CaMKII, PKA, and PKC pathways which, upon activation by Ca 2+ , lead to synaptic potentiation or depression. We adjusted model components from existing models of intracellular signalling into a single-compartment simulation framework. Furthermore, we propose a statistical model for the prevalence of different types of membrane-bound AMPA-receptor tetramers consisting of GluR1 and GluR2 subunits in proportions suggested by the biochemical signalling model, which permits the estimation of the AMPA-receptor-mediated maximal synaptic conductance. We show that our model can reproduce neuromodulator-gated spike-timing-dependent plasticity as observed in the visual cortex. Moreover, we demonstrate that our model can be fit to data from many cortical areas and that the resulting model parameters reflect the involvement of the pathways pinpointed by the underlying experimental studies. Our model explains the dependence of different forms of plasticity on the availability of different proteins and can be used for the study of mental disorder-associated impairments of cortical plasticity. Significance statementNeocortical synaptic plasticity has been studied experimentally in a number of cortical areas, showing how interactions between neuromodulators and post-synaptic proteins shape the outcome of the plasticity. On the other hand, non-detailed computational models of long-term plasticity, such as Hebbian rules of synaptic potentiation and depression, have been widely used in modelling of neocortical circuits. In this work, we bridge the gap between these two branches of neuroscience by building a detailed model of post-synaptic plasticity that can reproduce observations on cortical plasticity and provide biochemical meaning to the simple rules of plasticity. Our model can be used for predicting the effects of chemical or genetic manipulations of various intracellular signalling proteins on induction of plasticity in health and disease.

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Section: Modelling the Ca 2+ Inputs And Neuromodulatory Inputsmentioning

confidence: 99%

A unified computational model for cortical post-synaptic plasticity

Mäki‐Marttunen

Iannella

Edwards

et al. 2020

Preprint

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“…Our findings of the need of both LVA Ca 2+ channels and I h currents for the shunting effect of the I h channels are interesting for schizophrenia research since both I h and LVA Ca 2+ channels, alongside cholinergic and dopaminergic receptors, are products of risk genes of the mental disorder [Devor et al, 2017, Refisch et al, 2021, El Khoueiry et al, 2022]. Furthermore, neuromodulatory systems and their interaction likely play a crucial role in the pathophysiology of schizophrenia [Mäki-Marttunen et al, 2020]. Computational work like the one presented here offers a methodological approach to unify the different levels at which this and other mental disorders express their symptoms and phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Excitatory and inhibitory effects of HCN channel modulation on excitability of layer V pyramidal cells

Mäki‐Marttunen

Mäki-Marttunen

2022

Preprint

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Dendrites of cortical pyramidal cells are densely populated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, a.k.a. Ih channels. Ih channels are targeted by multiple neuromodulatory pathways, and thus are one of the key ion-channel populations regulating the pyramidal cell activity. Previous observations and theories attribute opposing effects of the Ih channels on neuronal excitability due to their mildly hyperpolarized reversal potential. These effects are difficult to measure experimentally due to the fine spatiotemporal landscape of the Ih activity in the dendrites, but computational models provide an efficient tool for studying this question in a reduced but generalizable setting. In this work, we build upon existing biophysically detailed models of thick-tufted layer V pyramidal cells and model the effects of over- and under-expression of Ih channels as well as their neuromodulation by dopamine (gain of Ih function) and acetylcholine (loss of Ih function). We show that Ih channels facilitate the action potentials of layer V pyramidal cells in response to proximal dendritic stimulus while they hinder the action potentials in response to distal dendritic stimulus at the apical dendrite. We also show that the inhibitory action of the Ih channels in layer V pyramidal cells is due to the interactions between Ih channels and a hot zone of low voltage-activated Ca2+ channels at the apical dendrite. Our simulations suggest that a combination of Ih-enhancing neuromodulation at the proximal apical dendrite and Ih-inhibiting modulation at the distal apical dendrite can increase the layer V pyramidal excitability more than any of the two neuromodulators alone. Our analyses uncover the effects of Ih-channel neuromodulation of layer V pyramidal cells at a single-cell level and shed light on how these neurons integrate information and enable higher-order functions of the brain.

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“…arousal regulation, effort allocation, uncertainty processing, etc.). Although norepinephrine has been linked to schizophrenia (M€ aki-Marttunen, Andreassen, & Espeseth, 2020;Maletic, Eramo, Gwin, Offord, & Duffy, 2017), it is not a neurotransmitter that is of current primary interest in the condition. However, given the general role the LC-NE plays for cortical function and development, a link with schizophrenia vulnerability is plausible.…”

Section: Pupil Baselinementioning

confidence: 99%

Pupil size and pupillary light reflex in early infancy: heritability and link to genetic liability to schizophrenia

Portugal

Taylor

Viktorsson

et al. 2021

Child Psychology Psychiatry

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Background: Measures based on pupillometry, such as the pupillary light reflex (PLR) and baseline pupil size, reflect physiological responses linked to specific neural circuits that have been implicated as atypical in some psychiatric and neurodevelopmental conditions. Methods: We investigated the contribution of genetic and environmental factors to the baseline pupil size and the PLR in 510 infant twins assessed at 5 months of age (281 monozygotic and 229 dizygotic pairs), and its associations with common genetic variants associated with neurodevelopmental (autism spectrum disorder and attention deficit hyperactivity disorder) and mental health (bipolar disorder, major depressive disorder and schizophrenia) conditions using genome-wide polygenic scores (GPSs). Results: Univariate twin modelling showed high heritability at 5 months for both pupil size (h 2 = .64) and constriction in response to light (h 2 = .62), and bivariate twin modeling indicated substantial independence between the genetic factors influencing each (r G = .38). A statistically significant positive association between infant tonic pupil size and the GPS for schizophrenia was found (b = .15, p = .024), while there was no significant association with the GPS for autism or any other GPSs. Conclusions: This study shows that some pupil measures are highly heritable in early infancy, although substantially independent in their genetic etiologies, and associated with common genetic variants linked to schizophrenia. It illustrates how genetically informed studies of infants may help us understand early physiological responses associated with psychiatric disorders which emerge much later in life.

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The role of norepinephrine in the pathophysiology of schizophrenia

Cited by 10 publications

References 258 publications

A unified computational model for cortical post-synaptic plasticity

A unified computational model for cortical post-synaptic plasticity

Excitatory and inhibitory effects of HCN channel modulation on excitability of layer V pyramidal cells

Pupil size and pupillary light reflex in early infancy: heritability and link to genetic liability to schizophrenia

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