Loss of Nogo-A, encoded by the schizophrenia risk gene Rtn4, reduces mGlu3 expression and causes hyperexcitability in hippocampal CA3 circuits

Berry, Stewart; Weinmann, Oliver; Fritz, Ann‐Kristina; Rust, Ruslan; Wolfer, David P; Gerber, Urs; Ster, Jeanne

doi:10.1371/journal.pone.0200896

Cited by 10 publications

(6 citation statements)

References 54 publications

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“…Moreover, by co-application of EGTA, we show that the increase in Ca 2+ dynamics upon Nogo-A loss of function is required for its effect on GABA A R localization at synapses. Our results also confirm the previously observed increase in excitatory synaptic transmission (Berry et al, 2018;Kellner et al, 2016; Figure 2) and a significant increase in the amount of AMPARs at synapses upon Nogo-A function-blocking. While an increase in [Ca 2+ ] i is associated with an increase in the diffusion coefficient of GABA A Rs (Bannai et al, 2009), high [Ca 2+ ] i results in a decrease in the movement of AMPARs due to their increased confinement (Borgdorff and Choquet, 2002;Heine et al, 2008).…”

Section: Discussionsupporting

confidence: 92%

Fast Regulation of GABAAR Diffusion Dynamics by Nogo-A Signaling

et al. 2019

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Precisely controlling the excitatory and inhibitory balance is crucial for the stability and informationprocessing ability of neuronal networks. However, the molecular mechanisms maintaining this balance during ongoing sensory experiences are largely unclear. We show that Nogo-A signaling reciprocally regulates excitatory and inhibitory transmission. Loss of function for Nogo-A signaling through S1PR2 rapidly increases GABA A R diffusion, thereby decreasing their number at synaptic sites and the amplitude of GABAergic mIPSCs at CA3 hippocampal neurons. This increase in GABA A R diffusion rate is correlated with an increase in Ca 2+ influx and requires the calcineurin-mediated dephosphorylation of the g2 subunit at serine 327. These results suggest that Nogo-A signaling rapidly strengthens inhibitory GABAergic transmission by restricting the diffusion dynamics of GABA A Rs. Together with the observation that Nogo-A signaling regulates excitatory transmission in an opposite manner, these results suggest a crucial role for Nogo-A signaling in modulating the excitation and inhibition balance to restrict synaptic plasticity.

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Section: Discussionsupporting

confidence: 92%

Fast Regulation of GABAAR Diffusion Dynamics by Nogo-A Signaling

et al. 2019

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“…For instance, GWAS data identified Rtn4 as a risk gene associated with schizophrenia. Knockout of its functional protein Nogo-A in mice led to hyperexcitability in CA3 circuits and downregulation of mGlu3 metabotropic glutamate receptors 82 . Such hyperactivity may potentially give rise to the enhancement in pattern completion hypothesized to be one mechanism for thought disorder in schizophrenia (Figure 2) 48 .…”

Section: Aberrant Goal Attractors In the Ca1mentioning

confidence: 99%

The Shallow Cognitive Map Hypothesis: A Hippocampal framework for Thought Disorder in Schizophrenia

Musa¹,

Khan²,

Mujahid³

et al. 2021

Preprint

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Memories are not formed in isolation. They are associated and organized into relational knowledge structures that allow coherent thought. Failure to express such coherent thought is a key hallmark of Schizophrenia. Here we explore the hypothesis that thought disorder arises from disorganized Hippocampal cognitive maps. In doing so, we combine insights from two key lines of investigation, one concerning the neural signatures of cognitive mapping, and another that seeks to understand lower-level cellular mechanisms of cognition within a dynamical systems framework. Specifically, we propose that multiple distinct pathological pathways converge on the shallowing of Hippocampal attractors, giving rise to disorganized Hippocampal cognitive maps and driving thought disorder. We discuss the available evidence at the computational, behavioural, network and cellular levels. We also outline testable predictions from this framework including how it could unify major chemical and psychological theories of schizophrenia and how it can provide a rationale for understanding the aetiology and treatment of the disease.

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“…For instance, GWAS data identified Rtn4 as a risk gene associated with Schizophrenia. Knockout of its functional protein Nogo-A in mice led to hyperexcitability in CA3 circuits and downregulation of mGlu3 metabotropic glutamate receptors 91 . Such hyperactivity may potentially give rise to the enhancement in pattern completion hypothesized to be one mechanism for thought disorder in Schizophrenia (Fig.…”

Section: Introductionmentioning

confidence: 99%

The shallow cognitive map hypothesis: A hippocampal framework for thought disorder in schizophrenia

et al. 2022

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Memories are not formed in isolation. They are associated and organized into relational knowledge structures that allow coherent thought. Failure to express such coherent thought is a key hallmark of Schizophrenia. Here we explore the hypothesis that thought disorder arises from disorganized Hippocampal cognitive maps. In doing so, we combine insights from two key lines of investigation, one concerning the neural signatures of cognitive mapping, and another that seeks to understand lower-level cellular mechanisms of cognition within a dynamical systems framework. Specifically, we propose that multiple distinct pathological pathways converge on the shallowing of Hippocampal attractors, giving rise to disorganized Hippocampal cognitive maps and driving conceptual disorganization. We discuss the available evidence at the computational, behavioural, network, and cellular levels. We also outline testable predictions from this framework, including how it could unify major chemical and psychological theories of schizophrenia and how it can provide a rationale for understanding the aetiology and treatment of the disease.

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Loss of Nogo-A, encoded by the schizophrenia risk gene Rtn4, reduces mGlu3 expression and causes hyperexcitability in hippocampal CA3 circuits

Cited by 10 publications

References 54 publications

Fast Regulation of GABAAR Diffusion Dynamics by Nogo-A Signaling

Fast Regulation of GABAAR Diffusion Dynamics by Nogo-A Signaling

The Shallow Cognitive Map Hypothesis: A Hippocampal framework for Thought Disorder in Schizophrenia

The shallow cognitive map hypothesis: A hippocampal framework for thought disorder in schizophrenia

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