Mice with exonic RELN deletion identified from a patient with schizophrenia have impaired visual discrimination learning and reversal learning in touchscreen operant tasks

Liao, Jingzhu; Dong, Geyao; Wulaer, Bolati; Sawahata, Masahito; Mizoguchi, Hideaki; Mori, Daisuke; Ozaki, Norio; Nabeshima, Toshitaka; Nagai, Taku; Yamada, Kiyofumi

doi:10.1016/j.bbr.2021.113569

Cited by 4 publications

(4 citation statements)

References 38 publications

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“…Mouse models reflecting these genetic deletions result in animals that exhibit aspects of neuropsychiatric disorders [156,162,[173][174][175]. Furthermore, dorsal forebrain-specific Dab1 knockout mice show symptoms such as hyperactivity and changes in their working memory, demonstrating that Reelin-Dab1 signaling is associated with SZ [176].…”

Section: Reelin In Schizophreniamentioning

confidence: 99%

“…Furthermore, dorsal forebrain-specific Dab1 knockout mice show symptoms such as hyperactivity and changes in their working memory, demonstrating that Reelin-Dab1 signaling is associated with SZ [176]. Mice carrying a deletion of exons 52 to 58 of RELN (Reln-del) showed several abnormalities in their cerebellar formation and in seeking behavior for social novelty, as well as impaired learning ability during reversal learning tasks [173,174]. In addition, the suppression or reduction of Reelin expression or of its downstream pathway in animal models exhibit features of SCZ, such as cognitive impairments, psychosis vulnerability, and learning deficits [64,177,178].…”

Section: Reelin In Schizophreniamentioning

confidence: 99%

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Reelin Signaling in Neurodevelopmental Disorders and Neurodegenerative Diseases

Joly-Amado,

Kulkarni,

Nash

2023

Brain Sciences

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Reelin is an extracellular matrix glycoprotein involved in neuronal migration during embryonic brain development and synaptic plasticity in the adult brain. The role of Reelin in the developing central nervous system has been extensively characterized. Indeed, a loss of Reelin or a disruption in its signaling cascade leads to neurodevelopmental defects and is associated with ataxia, intellectual disability, autism, and several psychiatric disorders. In the adult brain, Reelin is critically involved in neurogenesis and synaptic plasticity. Reelin’s signaling potentiates glutamatergic and GABAergic neurotransmission, induces synaptic maturation, and increases AMPA and NMDA receptor subunits’ expression and activity. As a result, there is a growing literature reporting that a loss of function and/or reduction of Reelin is implicated in numerous neurodegenerative diseases. The present review summarizes the current state of the literature regarding the implication of Reelin and Reelin-mediated signaling during aging and neurodegenerative disorders, highlighting Reelin as a possible target in the prevention or treatment of progressive neurodegeneration.

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Section: Reelin In Schizophreniamentioning

confidence: 99%

Section: Reelin In Schizophreniamentioning

confidence: 99%

Reelin Signaling in Neurodevelopmental Disorders and Neurodegenerative Diseases

Joly-Amado,

Kulkarni,

Nash

2023

Brain Sciences

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“…A touchscreen-based VD task for rodents was previously developed to provide a better translational approach across species and improve understanding of the cognitive impairments observed in various neuropsychiatric disorders (Horner et al, 2013). The training was performed using the touchscreen chamber system (Phenosys, Berlin, Germany; Brain Science Idea, Osaka, Japan) as described in our previous reports (Liao et al, 2021;Wulaer et al, 2018).…”

Section: Touchscreen-based Visual Discrimination (Vd) Taskmentioning

confidence: 99%

Rho kinase inhibitors ameliorate acute methamphetamine-induced cognitive impairment through the cortico-striatal circuit in mice

Liao

Wulaer

Mizoguchi

et al. 2022

Preprint

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Schizophrenia (SCZ) is a severe psychiatric disorder characterized by positive symptoms, negative symptoms, and cognitive deficits. Although its pathoetiology remains unclear, it is known to involve small GTPase signaling. Rho kinase, an effector of small GTPase Rho, is highly expressed in the brain and plays a major role in neurite elongation and neuronal architecture. This study used a touchscreen-based visual discrimination (VD) task to investigate the effects of Rho kinase inhibitors on cognitive impairment in a methamphetamine (METH)–treated mouse model of SCZ. Systemic injection of the Rho kinase inhibitor fasudil dose-dependently ameliorated METH-induced impairment of VD. Fasudil also significantly suppressed the increase in the number of c-Fos–positive cells in the medial prefrontal cortex (mPFC) and dorsomedial striatum (DMS) following METH treatment. Bilateral microinjections of Y-27632, the other Rho kinase inhibitor, into the mPFC or DMS significantly ameliorated the METH-induced impairment of VD. Two proteins downstream of Rho kinase, myosin phosphatase-targeting subunit 1 (MYPT1; Thr696) and myosin light chain kinase 2 (MLC2; Thr18/Ser19), exhibited increased phosphorylation in the mPFC and DMS, respectively, after METH treatment, and fasudil inhibited these increases. Both haloperidol and fasudil ameliorated the METH-induced impairment of VD, while clozapine had little effect. Both haloperidol and clozapine suppressed METH-induced hyperactivity, but fasudil had no effect. Finally, haloperidol and clozapine significantly suppressed the METH-induced increase in MYPT1 (Thr696) phosphorylation in the mPFC, but not in the DMS. Thus, the METH-induced cognitive function impairment was ameliorated by treatment with Rho kinase inhibitors, which may act via the cortico-striatal circuit.

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“…Rodent cognitive tasks based on touchscreen hardware have been developed to maximise translational validity with corresponding human tasks ( Bartko et al, 2011 ; Bussey et al, 2012 ; Nilsson et al, 2016a ; 2016b ; 2018 ; Wulaer et al, 2018 ; Zeleznikow-Johnston et al, 2018 ; Liao et al, 2022 ). A rodent version of the IGT (rGT; reviewed in van den Bos et al, 2014 ) has been validated for cross-species investigation of cognition within the Research Domain Criteria (RDoC)/Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) cognitive constructs ( Cope et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

The schizophrenia risk gene Map2k7 regulates responding in a novel contingency-shifting rodent touchscreen gambling task

Openshaw

Pratt

Morris

2022

Disease Models &Amp; Mechanisms

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In schizophrenia, subjects show reduced ability to evaluate and update risk/reward contingencies, showing correspondingly suboptimal performance in the Iowa gambling task. JNK signalling gene variants are associated with schizophrenia risk, and JNK modulates aspects of cognition. We therefore studied the performance of mice hemizygous for genetic deletion of the JNK activator MKK7 (Map2k7+/− mice) in a touchscreen version of the Iowa gambling task, additionally incorporating a novel contingency-switching stage. Map2k7+/− mice performed slightly better than wild-type (WT) littermates in acquisition and performance of the task. Although Map2k7+/− mice adapted well to subtle changes in risk/reward contingencies, they were profoundly impaired when the positions of ‘best’ and ‘worst’ choice selections were switched, and still avoided the previous ‘worst’ choice location weeks after the switch. This demonstrates a precise role for MKK7–JNK signalling in flexibility of risk/reward assessment and suggests that genetic variants affecting this molecular pathway may underlie impairment in this cognitive domain in schizophrenia. Importantly, this new contingency shift adaptation of the rodent touchscreen gambling task has translational utility for characterising these cognitive subprocesses in models of neuropsychiatric disorders.

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Mice with exonic RELN deletion identified from a patient with schizophrenia have impaired visual discrimination learning and reversal learning in touchscreen operant tasks

Cited by 4 publications

References 38 publications

Reelin Signaling in Neurodevelopmental Disorders and Neurodegenerative Diseases

Reelin Signaling in Neurodevelopmental Disorders and Neurodegenerative Diseases

Rho kinase inhibitors ameliorate acute methamphetamine-induced cognitive impairment through the cortico-striatal circuit in mice

The schizophrenia risk gene Map2k7 regulates responding in a novel contingency-shifting rodent touchscreen gambling task

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