Kalirin as a Novel Treatment Target for Cognitive Dysfunction in Schizophrenia

Mould, Arne W.; Al‐Juffali, Noura; Delft, Annette von; Brennan, P.E.; Tunbridge, Elizabeth M.

doi:10.1007/s40263-021-00884-z

Cited by 10 publications

(8 citation statements)

References 125 publications

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“…Kalirin-7 mRNA expression and protein levels in the prefrontal cortex were also decreased in Scz patients (Hill et al, 2006;Mould et al, 2022).…”

Section: Postsynaptic Sidementioning

confidence: 91%

“…The RhoGTAPase family proteins are regulated by GEFs (guanine nucleotide exchange factors) and GAPs (GTPase‐activating proteins). Genes encoding many RhoGAP family proteins (ARGHAP) and GEF family proteins, such as Kalirin‐7, have been associated with Scz (Mandela & Ma, 2012; Mould et al., 2022; Nakazawa et al., 2016; Niftullayev & Lamarche‐Vane, 2019). These findings suggest that abnormalities in the regulation of actin cytoskeleton proteins may underlie the disruption in dendritic spine morphology and spine loss in Scz (Figure 3).…”

Section: Structural Changes Of Synapses In Schizophreniamentioning

confidence: 99%

“…Animal studies have shown a reduction in AMPAR current in kalrn knockout mice and a reduction in locomotor hyperactivity, and prepulse inhibition has also been observed in these mice (Cahill et al., 2009; Wang et al., 2013). Kalirin‐7 mRNA expression and protein levels in the prefrontal cortex were also decreased in Scz patients (Hill et al., 2006; Mould et al., 2022). These findings indicate the role of Kalirin‐7 in impaired spinogenesis and Scz.…”

Section: Molecular and Functional Changes In Synapsesmentioning

confidence: 99%

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Synaptic dysfunction in schizophrenia

Mısır

Akay

2023

Synapse

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Schizophrenia is a chronic disease presented with psychotic symptoms, negative symptoms, impairment in the reward system, and widespread neurocognitive deterioration.Disruption of synaptic connections in neural circuits is responsible for the disease's development and progression. Because deterioration in synaptic connections results in the impaired effective processing of information. Although structural impairments of the synapse, such as a decrease in dendritic spine density, have been shown in previous studies, functional impairments have also been revealed with the development of genetic and molecular analysis methods. In addition to abnormalities in protein complexes regulating exocytosis in the presynaptic region and impaired vesicle release, especially, changes in proteins related to postsynaptic signaling have been reported.In particular, impairments in postsynaptic density elements, glutamate receptors, and ion channels have been shown. At the same time, effects on cellular adhesion molecular structures such as neurexin, neuroligin, and cadherin family proteins were detected. Of course, the confusing effect of antipsychotic use in schizophrenia research should also be considered. Although antipsychotics have positive and negative effects on synapses, studies indicate synaptic deterioration in schizophrenia independent of drug use. In this review, the deterioration in synapse structure and function and the effects of antipsychotics on the synapse in schizophrenia will be discussed.

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“…Kalirin-7 mRNA expression and protein levels in the prefrontal cortex were also decreased in Scz patients (Hill et al, 2006;Mould et al, 2022).…”

Section: Postsynaptic Sidementioning

confidence: 91%

Section: Structural Changes Of Synapses In Schizophreniamentioning

confidence: 99%

Section: Molecular and Functional Changes In Synapsesmentioning

confidence: 99%

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Synaptic dysfunction in schizophrenia

Mısır

Akay

2023

Synapse

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“…In recent decades, cognitive impairment has been recognized as a core symptom of schizophrenia (Liddle, 2019; McCutcheon et al., 2020; Oliver et al., 2022; Robison et al., 2020) and received more attention than positive and negative symptoms in recent years (Bellani et al., 2019; Jones & Harvey, 2020; Kharawala et al., 2022; Mould et al., 2022; Sciortino et al., 2021). Cognitive bias is defined as a methodical orientation toward processing, selecting, appraising, and remembering specific information (Campbell et al., 2017; Landucci & Lamperti, 2021; O'Sullivan & Schofield, 2018; Ozdemir & Finkelstein, 2018).…”

Section: Introductionmentioning

confidence: 99%

Validation of a modified Chinese‐language version of the Davos Assessment of Cognitive Biases Scale (MCL‐DACOBS) in a sample of Chinese patients with schizophrenia

Chen

Tian

et al. 2023

Brain and Behavior

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IntroductionThe Davos Assessment of Cognitive Biases Scale (DACOBS) is widely used to assess cognitive biases in patients who have schizophrenia. However, the lack of a modified Chinese‐language version of the DACOBS (MCL‐DACOBS) precludes Chinese schizophrenic patients from treatment aimed at normalizing cognitive biases, impacting their prognosis. Here, we aimed to produce a DACOBS for China and test the validity and reliability of the resultant MCL‐DACOBS.MethodsEighteen researchers collaborated to develop the MCL‐DACOBS: A total of 15 researchers modified and translated the English version of the DACOBS, 1 native‐English‐speaking researcher back‐translated the scale, and 2 Chinese sinologists localized and optimized the language of the MCL‐DACOBS. Forty‐two volunteers checked the scale items’ comprehensibility, and the two sinologists performed further localization and optimization based on their feedback. The final version of the MCL‐DACOBS used in this study was thus derived from the harmonized English‐language version of the scale. Confirmatory factor analyses (CFAs) were used to examine the best latent structure of the MCL‐DACOBS. Cronbach's α and intraclass correlation coefficients (ICCs) were used to check the reliability. The discriminative ability of the MCL‐DACOBS was assessed according to the area under the receiver operating characteristic curve.ResultsThe CFA showed that all items loaded onto factors with loadings >0.400. A two‐factor structure showed a good model fit (root mean square error of approximation = .018, Tucker–Lewis index = .978, comparative fit index = .984). Promax rotation demonstrated that each item had a high factor load (0.432–0.774). Cronbach's α coefficient and ICC for the MCL‐DOCABS were .965 and .957, respectively, indicating that the scale has ideal reliability.ConclusionThe MCL‐DACOBS has good validity and good reliability, and its psychometric properties indicate that it is a valid tool for measuring cognitive biases in Chinese patients with schizophrenia.

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“…The Rho GTPase family plays a role in spine morphology by regulating actin dynamics [23]. It is associated with psychiatric diseases such as schizophrenia and depression, and also with neurodevelopmental disorders including autism spectrum disorders and intellectual disabilities [24][25][26][27][28][29][30][31]. Variants in genes upstream of the Rho GTPase family, such as KALRN and p250GAP, have been reported to be associated with schizophrenia [25,27].…”

Section: Introductionmentioning

confidence: 99%

Genomic and Reverse Translational Analysis Discloses a Role for Small GTPase RhoA Signaling in the Pathogenesis of Schizophrenia: Rho-Kinase as a Novel Drug Target

Tanaka,

Yamada

2023

IJMS

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Schizophrenia is one of the most serious psychiatric disorders and is characterized by reductions in both brain volume and spine density in the frontal cortex. RhoA belongs to the RAS homolog (Rho) family and plays critical roles in neuronal development and structural plasticity via Rho-kinase. RhoA activity is regulated by GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs). Several variants in GAPs and GEFs associated with RhoA have been reported to be significantly associated with schizophrenia. Moreover, several mouse models carrying schizophrenia-associated gene variants involved in RhoA/Rho-kinase signaling have been developed. In this review, we summarize clinical evidence showing that variants in genes regulating RhoA activity are associated with schizophrenia. In the last half of the review, we discuss preclinical evidence indicating that RhoA/Rho-kinase is a potential therapeutic target of schizophrenia. In particular, Rho-kinase inhibitors exhibit anti-psychotic-like effects not only in Arhgap10 S490P/NHEJ mice, but also in pharmacologic models of schizophrenia (methamphetamine- and MK-801-treated mice). Accordingly, we propose that Rho-kinase inhibitors may have antipsychotic effects and reduce cognitive deficits in schizophrenia despite the presence or absence of genetic variants in small GTPase signaling pathways.

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Kalirin as a Novel Treatment Target for Cognitive Dysfunction in Schizophrenia

Cited by 10 publications

References 125 publications

Synaptic dysfunction in schizophrenia

Synaptic dysfunction in schizophrenia

Validation of a modified Chinese‐language version of the Davos Assessment of Cognitive Biases Scale (MCL‐DACOBS) in a sample of Chinese patients with schizophrenia

Genomic and Reverse Translational Analysis Discloses a Role for Small GTPase RhoA Signaling in the Pathogenesis of Schizophrenia: Rho-Kinase as a Novel Drug Target

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