Potential synergistic action of 19 schizophrenia risk genes in the thalamus

Richard, Edwin A.; Khlestova, Elizaveta; Nanu, Roshan; Lisman, John

doi:10.1016/j.schres.2016.09.008

Cited by 12 publications

(10 citation statements)

References 70 publications

(82 reference statements)

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“…a reduction in sleep spindles 75 . Our results bring further evidence to the link between thalamic NMDAR hypofunction and the emergence of aberrant thalamic oscillations related to schizophrenic symptoms 38 , and are also in line with the proposed role of low-threshold Ca V 3 channel dysfunction in schizophrenia 76 , 77 .…”

Section: Discussionsupporting

confidence: 88%

Cortical afferents onto the nucleus Reticularis thalami promote plasticity of low-threshold excitability through GluN2C-NMDARs

Fernandez

Pellegrini

Vantomme

et al. 2017

Sci Rep

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Thalamus and cortex represent a highly integrated processing unit that elaborates sensory representations. Interposed between cortex and thalamus, the nucleus Reticularis thalami (nRt) receives strong cortical glutamatergic input and mediates top-down inhibitory feedback to thalamus. Despite growing appreciation that the nRt is integral for thalamocortical functions from sleep to attentional wakefulness, we still face considerable gaps in the synaptic bases for cortico-nRt communication and plastic regulation. Here, we examined modulation of nRt excitability by cortical synaptic drive in Ntsr1-Cre x ChR2tg/+ mice expressing Channelrhodopsin2 in layer 6 corticothalamic cells. We found that cortico-nRt synapses express a major portion of NMDA receptors containing the GluN2C subunit (GluN2C-NMDARs). Upon repetitive photoactivation (10 Hz trains), GluN2C-NMDARs induced a long-term increase in nRt excitability involving a potentiated recruitment of T-type Ca2+ channels. In anaesthetized mice, analogous stimulation of cortical afferents onto nRt produced long-lasting changes in cortical local field potentials (LFPs), with delta oscillations being augmented at the expense of slow oscillations. This shift in LFP spectral composition was sensitive to NMDAR blockade in the nRt. Our data reveal a novel mechanism involving plastic modification of synaptically recruited T-type Ca2+ channels and nRt bursting and indicate a critical role for GluN2C-NMDARs in thalamocortical rhythmogenesis.

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Section: Discussionsupporting

confidence: 88%

Cortical afferents onto the nucleus Reticularis thalami promote plasticity of low-threshold excitability through GluN2C-NMDARs

Fernandez

Pellegrini

Vantomme

et al. 2017

Sci Rep

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“…Given the overwhelming evidence of thalamic dysfunction in schizophrenia, it is important to consider how the identified genetic risks could be mechanistically involved in the pathogenic processes. A previous attempt was made to combine identified common risk variants and CNVs into a thalamus-centered model of schizophrenia ( Richard et al, 2017 ). Here, we focus on thalamic aspects of the 22q11.2 microdeletion, a CNV that confers one of the strongest genetic predictors of schizophrenia, and its mechanistic connection to several common gene variants identified in GWAS ( Ripke et al, 2014 ) [e.g., DRD2, SERCA2 (encoded by the ATP2A gene) and CAV3.3 (encoded by the CACNA1I gene)].…”

Section: Schizophrenia-risk Genes and Mechanisms Of Thalamic Dysfunctionmentioning

confidence: 99%

A Case for Thalamic Mechanisms of Schizophrenia: Perspective From Modeling 22q11.2 Deletion Syndrome

Jiang

Patton

Zakharenko

2021

Front. Neural Circuits

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Schizophrenia is a severe, chronic psychiatric disorder that devastates the lives of millions of people worldwide. The disease is characterized by a constellation of symptoms, ranging from cognitive deficits, to social withdrawal, to hallucinations. Despite decades of research, our understanding of the neurobiology of the disease, specifically the neural circuits underlying schizophrenia symptoms, is still in the early stages. Consequently, the development of therapies continues to be stagnant, and overall prognosis is poor. The main obstacle to improving the treatment of schizophrenia is its multicausal, polygenic etiology, which is difficult to model. Clinical observations and the emergence of preclinical models of rare but well-defined genomic lesions that confer substantial risk of schizophrenia (e.g., 22q11.2 microdeletion) have highlighted the role of the thalamus in the disease. Here we review the literature on the molecular, cellular, and circuitry findings in schizophrenia and discuss the leading theories in the field, which point to abnormalities within the thalamus as potential pathogenic mechanisms of schizophrenia. We posit that synaptic dysfunction and oscillatory abnormalities in neural circuits involving projections from and within the thalamus, with a focus on the thalamocortical circuits, may underlie the psychotic (and possibly other) symptoms of schizophrenia.

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“…Our sensitivity analysis characterized excitation-inhibition balance as a key effective parameter regulating thalamic dynamics and computation, with preferential sensitivity to perturbations involving RE neurons. The TRN has emerged as a key site of vulnerability associated with neurodevelopmental disorders and as a target for therapeutics (Krol et al, 2018; Huguenard and McCormick, 2007; Fagerberg et al, 2014; Ritter-Makinson et al, 2019; Ahrens et al, 2015; Wells et al, 2016; Murray and Anticevic, 2017; Richard et al, 2017). Incorporation of additional biophysical processes in the model will likely be important for simulating effects of disease and pharmacology, to link cellular and synaptic perturbations to deficits in perceptual and cognitive functions.…”

Section: Discussionmentioning

confidence: 99%

Computational Circuit Mechanisms Underlying Thalamic Control of Attention

Lam

Wimmer

et al. 2020

Preprint

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SummaryThe thalamus is a key brain structure engaged in attentional functions, such as selectively amplifying task-relevant signals of one sensory modality while filtering distractors of another. To investigate computational mechanisms of attentional modulation, we developed a biophysically grounded thalamic reticular circuit model, comprising excitatory thalamocortical and inhibitory reticular neurons, which captures characteristic neurophysiological observations from the alert behaving animals. Top-down attentional control inputs onto reticular neurons effectively modulate thalamic gain and enhance downstream readout, to improve performance across detection, discrimination, and cross-modal task paradigms. Heterogeneity of thalamic responses plays an essential role in downstream decoding during attentional modulation. Dynamical systems analysis explains why reticular neurons are an especially potent site for top-down control, as implicated by experiments. Perturbation analysis reveals excitation-inhibition ratio as an effective parameter governing thalamic processing. These findings establish experimentally testable circuit mechanisms for attentional control in thalamus, with implications for distributed neural control of cognitive processing.

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Potential synergistic action of 19 schizophrenia risk genes in the thalamus

Cited by 12 publications

References 70 publications

Cortical afferents onto the nucleus Reticularis thalami promote plasticity of low-threshold excitability through GluN2C-NMDARs

Cortical afferents onto the nucleus Reticularis thalami promote plasticity of low-threshold excitability through GluN2C-NMDARs

A Case for Thalamic Mechanisms of Schizophrenia: Perspective From Modeling 22q11.2 Deletion Syndrome

Computational Circuit Mechanisms Underlying Thalamic Control of Attention

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