The effect of constitutive over-expression of insulin-like growth factor 1 on the cognitive function in aged mice

Hu, Ankang; Hu, Yuan; Wu, Lianlian; Chen, Renjin; Chen, Quangang; Zhang, Tengye; Wang, Zhenzhen; Liu, Peng; Zhu, Xiaorong

doi:10.1016/j.brainres.2015.11.010

Cited by 22 publications

(18 citation statements)

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“…Here, we identified IGF-1R (a neurotrophin receptor) and TLR4 (a proinflammatory receptor) as potential non-neurotransmitter regulators of CaMKIIα function. While IGF-1R can increase CaMKIIα (Hu et al, 2016; Le Grevès et al, 2005; Dou et al, 2005), TLR4 can reduce CaMKIIα activity (Mémet, 2006; Kaltschmidt et al, 2005). However, how IGF-1R/TLR4 cross-talk in CaMKIIα function affects NMDAR activity in schizophrenia is poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…CaMKIIα is involved in inflammatory signaling that is linked with toll-like receptor 4 (TLR4/NF-κB) (Kaltschmidt et al, 2005; Mémet, 2006). Additionally, it acts downstream of IGF-1R-Ras/Raf pathway to regulate calcium-mediated synaptic activity of NMDAR (Hu et al, 2016; Le Grevès et al, 2005; Dou et al, 2005). Based on these propositions, it is logical to speculate that synaptic and inflammatory activity of CaMKIIα are not mutually exclusive.…”

Section: Introductionmentioning

confidence: 99%

“…Among these, IGF-1R may alter CaMKIIα expression through Wnt/GSK3 and Ras/Raf signaling in growth, synaptic function, inflammation, and cell death (Pereira et al, 2008). Furthermore, both IGF-1R and CaMKIIα promotes pre- and post-synaptic calcium movement linked to NMDAR function in the hippocampus during long-term potentiation (LTP) and cognition (Cassilhas et al, 2012; Hu et al, 2016). In addition to the control of growth and aging, a recent study demonstrates the significance of IGF-1R signaling in presynaptic calcium release and glutamatergic neurotransmission.…”

Section: Introductionmentioning

confidence: 99%

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CaMKIIα expression in a mouse model of NMDAR hypofunction schizophrenia: Putative roles for IGF-1R and TLR4

Ogundele

Lee

2018

Brain Research Bulletin

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Schizophrenia (SCZ) is a neuropsychiatric disorder that is linked to social behavioral deficits and other negative symptoms associated with hippocampal synaptic dysfunction. Synaptic mechanism of schizophrenia is characterized by loss of hippocampal N-Methyl-d-Aspartate Receptor (NMDAR) activity (NMDAR hypofunction) and dendritic spines. Previous studies show that genetic deletion of hippocampal synaptic regulatory calcium-calmodulin dependent kinase II alpha (CaMKIIα) cause synaptic and behavioral defects associated with schizophrenia in mice. Although CaMKIIα is involved in modulation of NMDAR activity, it is equally linked to inflammatory and neurotropin signaling in neurons. Based on these propositions, we speculate that non-neurotransmitter upstream receptors associated with neurotropic and inflammatory signaling activities of CaMKIIα may alter its synaptic function. Besides, how these receptors (i.e. inflammatory and neurotropic receptors) alter CaMKIIα function (phosphorylation) relative to hippocampal NMDAR activity in schizophrenia is poorly understood. Here, we examined the relationship between toll-like receptor (TLR4; inflammatory), insulin-like growth factor receptor 1 (IGF-1R; neurotropic) and CaMKIIα expression in the hippocampus of behaviorally deficient schizophrenic mice after we induced schizophrenia through NMDAR inhibition. Schizophrenia was induced in WT (C57BL/6) mice through intraperitoneal administration of 30mg/Kg ketamine (NMDAR antagonist) for 5days (WT/SCZ). Five days after the last ketamine treatment, wild type schizophrenic mice show deficiencies in sociability and social novelty behavior. Furthermore, there was a significant decrease in hippocampal CaMKIIα (p<0.001) and IGF-1R (p<0.001) expression when assessed through immunoblotting and confocal immunofluorescence microscopy. Additionally, WT schizophrenic mice show an increased percentage of phosphorylated CaMKIIα in addition to upregulated TLR4 signaling (TLR4, NF-κB, and MAPK/ErK) in the hippocampus. To ascertain the functional link between TLR4, IGF-1R and CaMKIIα relative to NMDAR hypofunction in schizophrenia, we created hippocampal-specific TLR4 knockdown mouse using AAV-driven Cre-lox technique (TLR4 KD). Subsequently, we inhibited NMDAR function in TLR4 KD mice in an attempt to induce schizophrenia (TLR4 KD SCZ). Interestingly, IGF-1R and CaMKIIα expressions were preserved in the TLR4 KD hippocampus after attenuation of NMDAR function. Furthermore, TLR4 KD SCZ mice showed no prominent defects in sociability and social novelty behavior when compared with the control (WT). Our results show that a sustained IGF-1R expression may preserve the synaptic activity of CaMKIIα while TLR4 signaling ablates hippocampal CaMKIIα expression in NMDAR hypofunction schizophrenia. Together, we infer that IGF-1R depletion and increased TLR4 signaling are non-neurotransmitter pro-schizophrenic cues that can reduce synaptic CaMKIIα activity in a pharmacologic mouse model of schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CaMKIIα expression in a mouse model of NMDAR hypofunction schizophrenia: Putative roles for IGF-1R and TLR4

Ogundele

Lee

2018

Brain Research Bulletin

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“…Thus, variations in IGF-1R may be attributable to synaptic modifications implicated in the pathophysiology of memory formation and retrieval in stress (Zhao et al, 1999; Freude et al, 2009). Additionally, IGF-1R governs neurotransmitter interactions involved in mood, emotion, addiction, reward, memory, and anxiety (Hu et al, 2016; Gontier et al, 2015; Takeuchi et al, 2002; Zhang et al, 2014; Kleinridders et al, 2014; Sun and Goodkin, 2016; Pan et al, 2013). Previous studies have shown that the activation IGF-1R promotes the presynaptic release of glutamate and the cellular synthesis of tyrosine hydroxylase; which favor dopaminergic neurotransmission (Duan et al, 2014; Dall’Igna et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, IGF-1R is known to directly regulate the activity of dopamine and glutamate at post-synaptic terminals by directly altering the activity of N-methyl-D-aspartate receptor (NMDAR R) and dopaminergic D2R (la Cour et al, 2011; Quesada et al, 2011; Kelinridders et al, 2014). Thus, some of the effect on IGF-1/IGF-1R on complex behaviors may be linked to its role in the combined regulation of dopaminergic and glutamatergic neurotransmission (Bouallegue et al, 2009; Hu et al, 2016; Gao et al, 2014; Davis et al, 2000; Dong and Zhang, 2015; Rusch et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

Stress-altered synaptic plasticity and DAMP signaling in the hippocampus-PFC axis; elucidating the significance of IGF-1/IGF-1R/CaMKIIα expression in neural changes associated with a prolonged exposure therapy

et al. 2017

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Traumatic stress patients showed significant improvement in behavior after a prolonged exposure to an unrelated stimulus. This treatment method attempts to promote extinction of the fear memory associated with the initial traumatic experience. However, the subsequent prolonged exposure to such stimulus creates an additional layer of neural stress. Although the mechanism remains unclear, prolonged exposure therapy (PET) likely involve changes in synaptic plasticity, neurotransmitter function and inflammation; especially in parts of the brain concerned with the formation and retrieval of fear memory (Hippocampus and Prefrontal Cortex: PFC). Since certain synaptic proteins are also involved in danger associated molecular pattern signaling (DAMP), we identified the significance of IGF-1/IGF-1R/CaMKIIα expression as a potential link between the concurrent progression of synaptic and inflammatory changes in stress. Thus, a comparison between IGF-1/IGF-1R/CaMKIIα, synaptic and DAMP proteins in stress and PET may highlight the significance of PET on synaptic morphology and neuronal inflammatory response. In behaviorally characterized Sprague Dawley rats, there was a significant decline in neural IGF-1 (p<0.001), hippocampal (p<0.001) and cortical (p<0.05) IGF-1R expression. These animals showed a significant loss of presynaptic markers (synaptophysin; p<0.001), and changes in neurotransmitters (VGLUT2, Tyrosine hydroxylase, GABA, ChAT). Furthermore, naïve stressed rats recorded a significant decrease in post-synaptic marker (PSD-95; p<0.01) and synaptic regulator (CaMKIIα; p<0.001). As part of the synaptic response to a decrease in brain CaMKIIα, small ion conductance channel (KCa2.2) was upregulated in the brain of naïve stressed rats (p<0.01). After a PET, an increase in IGF-1 (p<0.05) and IGF-1R was recorded in the Stress-PET group (p<0.001). As such, hippocampal (p<0.001), but not cortical (ns) synaptophysin expression increased in Stress-PET. Although PSD-95 was relatively unchanged in the hippocampus and PFC, CaMKIIα (p<0.001) and KCa2.2 (p<0.01) were upregulated in Stress-PET, and may be involved in extinction of fear memory-related synaptic potentials. These changes were also associated with a normalized neurotransmitter function, and a significant reduction in open space avoidance; when the animals were assessed in elevated plus maze (EPM). In addition to a decrease in IGF-1/IGF-1R, an increase in activated hippocampal and cortical microglia was seen in stress (p<0.05) and after a PET (Stress-PET; p<0.001). Furthermore, this was linked with a significant increase in HMGB1 (Hippocampus: p<0.001, PFC: p<0.05) and TLR4 expression (Hippocampus: p<0.01; PFC: ns) in the neurons. Taken together, this study showed that traumatic stress and subsequent PET involves an event dependent alteration of IGF1/IGF-1R/CaMKIIα. Firstly, we showed a direct relationship between IGF-1/IGF-1R expression, presynaptic function (synaptophysin) and neurotransmitter activity in stress and PET. Secondly, we identified the possible role of C...

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Effects of somatotropic axis on cognitive dysfunction of obstructive sleep apnea

Qin

et al. 2019

Sleep Breath

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The effect of constitutive over-expression of insulin-like growth factor 1 on the cognitive function in aged mice

Cited by 22 publications

References 54 publications

CaMKIIα expression in a mouse model of NMDAR hypofunction schizophrenia: Putative roles for IGF-1R and TLR4

CaMKIIα expression in a mouse model of NMDAR hypofunction schizophrenia: Putative roles for IGF-1R and TLR4

Stress-altered synaptic plasticity and DAMP signaling in the hippocampus-PFC axis; elucidating the significance of IGF-1/IGF-1R/CaMKIIα expression in neural changes associated with a prolonged exposure therapy

Effects of somatotropic axis on cognitive dysfunction of obstructive sleep apnea

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