Hippocampal volume and the AKT signaling system in first-episode schizophrenia

Szamosi, András; Kelemen, Ogúz; Kéri, Szabolcs

doi:10.1016/j.jpsychires.2011.12.005

Cited by 26 publications

(23 citation statements)

References 54 publications

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“…in 2004, who identified a multi-single-nucleotide polymorphism (SNP) in patients with schizophrenia. Additionally, these researchers found reduced levels of Akt1 expression in patients with schizophrenia, a finding that has been confirmed in several subsequent studies (Balu et al 2012; Blasi et al 2012; Szamosi et al 2012). Genetic variations in Akt1 have been linked to altered brain physiology, behavior and cognition.…”

Section: Introductionsupporting

confidence: 58%

Electrophysiological and behavioral responses to ketamine in mice with reduced Akt1 expression

et al. 2013

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Rationale A number of studies have associated reduced Akt1 expression with vulnerability for schizophrenia. Although mice with deletion of a single copy of the Akt1 gene (Akt1+/−) show reduced Akt1 expression relative to wild-type (WT) animals, the extent to which these mice show schizophrenia-like phenotypic changes and/or increased susceptibility to epigenetic or non-genetic factors related to schizophrenia is unknown. Objectives Mutant mice were assessed on electroencephalographic/event related potential (EEG/ERP) and behavioral (acoustic startle and pre-pulse inhibition) measures relevant to schizophrenia. Mice were also assessed following exposure to the NMDA receptor antagonist ketamine, a potent psychotomimetic drug, in order to assess the role of reduced Akt1 expression as a vulnerability factor for schizophrenia. Methods Akt1+/−, Akt1−/− and WT mice received a series of paired-click, white noise stimuli, following ketamine (50 mg/kg) and saline injections. EEG was analyzed for ERPs and event-related power. Akt1+/− and WT mice were also assessed on PPI following ketamine (50 mg/kg) or saline injection. Results Akt1+/− and Akt1−/− mice displayed reduced amplitude of the P20 component of the ERP to the first click of a paired click stimulus, as well as reduced S1-S2 difference for P20 and N40 components, following ketamine. Mutant mice also showed increased reduction in gamma synchrony and theta suppression following ketamine. Akt1+/− mice displayed reduced pre-pulse inhibition. Conclusions Reduced genetic expression of Akt1 facilitated ketamine-induced changes of EEG and behavior in mice, suggesting that reduced Akt1 expression can serve as a vulnerability factor for schizophrenia.

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Section: Introductionsupporting

confidence: 58%

Electrophysiological and behavioral responses to ketamine in mice with reduced Akt1 expression

et al. 2013

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“…ErbB3, but not ErbB2, mRNA levels were significantly reduced in the lymphoblasts of schizophrenia patients, and it was not associated with the ErbB4 risk haplotype 24 . We showed that impaired NRG1-induced B cell activation correlates with weak physiological habituation of arousal and paranoid ideas 25 , abnormal gating of perceptual information 26 , and decreased hippocampal volume in schizophrenia 27 . Furthermore, additional evidence from animal and human studies suggests that NRG1 may be a key factor in the interplay of neurodevelopment, synaptic plasticity, glutamatergic/GABA-ergic neurotransmission, and immunological mechanisms in schizophrenia 28–35 .…”

Section: Introductionmentioning

confidence: 86%

Uniting the neurodevelopmental and immunological hypotheses: Neuregulin 1 receptor ErbB and Toll-like receptor activation in first-episode schizophrenia

Kéri

Szabó

Kelemen

2017

Sci Rep

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Current pathophysiological models of schizophrenia focus on neurodevelopmental and immunological mechanisms. We investigated a molecular pathway traditionally linked to the neurodevelopmental hypothesis (neuregulin 1 - ErbB), and pathogen-associated pattern recognition receptors associated with the immune hypothesis (Toll-like receptors, TLRs). We recruited 42 first-episode, drug-naïve patients with schizophrenia and 42 matched healthy control subjects. In monocytes TLR4/TLR5 and ErbB expressions were measured with flow-cytometry. Pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and the anti-inflammatory cytokine IL-10 were determined following the stimulation of TLR4/TLR5 and ErbB. Results revealed increased TLR4/TLR5 and decreased ErbB4 expression in schizophrenia relative to the control subjects. The expression of ErbB2 and ErbB3 receptors was unaltered in schizophrenia. TLR4 stimulation resulted in lower pro-inflammatory cytokine production in schizophrenia compared to the control levels, whereas the stimulation of ErbB by neuregulin 1 led to higher pro-inflammatory cytokine levels in patients with schizophrenia relative to the control group. In healthy controls, ErbB activation was associated with a marked production of IL-10, which was dampened in schizophrenia. These results indicate that the stimulation of TLR4 and ErbB induces opposite pro-inflammatory cytokine responses in schizophrenia.

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“…In addition, many studies have found genetic association between AKT1 genetic variants and schizophrenia (Emamian et al, 2004; Ikeda et al, 2004; Schwab et al, 2005; Bajestan et al, 2006). A recent study has shown an association between decrease in phosphorylated AKT--total AKT ratio and reduced hippocampal volume in first episode schizophrenia subjects (Szamosi et al, 2012). Significant decreases in protein levels of members in ERK signaling pathway such as Rap1, B-Raf, MEK1, MEK2, ERK1/2 and RSK1 were found in prefrontal cortex of schizophrenia subjects (Yuan et al, 2010).…”

Section: Neuroprotective Roles Of Bdnf/trkb Signalingmentioning

confidence: 99%

BDNF–TrkB signaling and neuroprotection in schizophrenia

Pandya¹,

Kutiyanawalla²,

Pillai³

2013

Asian Journal of Psychiatry

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Neurotrophins such as brain-derived neurotropic factor (BDNF), play critical role in neuronal survival, synaptic plasticity and cognitive functions. BDNF is known to mediate its action through various intracellular signaling pathways triggered by activation of tyrosine kinase receptor B (TrkB). Evidence from clinical as well as pre-clinical studies indicate alterations in BDNF signaling in schizophrenia. Moreover, several antipsychotic drugs have time-dependent effects on BDNF levels in both schizophrenia subjects and animal models of schizophrenia. Given the emerging interest in neuroplasticity in schizophrenia understanding the neuroprotective and cell survival roles of BDNF signaling will enhance our knowledge of its diverse effects, which may lead to more effective treatments for schizophrenia. This article will present an overview of recent findings on the role of BDNF signaling in the pathophysiology and treatment of schizophrenia, with a special focus on its neuroprotective effects.

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Hippocampal volume and the AKT signaling system in first-episode schizophrenia

Abstract: Activation of the AKT system is specifically associated with hippocampal volume in first-episode schizophrenia, which provides further evidence for the pivotal role of this messenger system in the pathophysiology of psychotic disorders.

Cited by 26 publications

References 54 publications

Electrophysiological and behavioral responses to ketamine in mice with reduced Akt1 expression

Electrophysiological and behavioral responses to ketamine in mice with reduced Akt1 expression

Uniting the neurodevelopmental and immunological hypotheses: Neuregulin 1 receptor ErbB and Toll-like receptor activation in first-episode schizophrenia

BDNF–TrkB signaling and neuroprotection in schizophrenia

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