The VGF-derived peptide TLQP62 produces antidepressant-like effects in mice via the BDNF/TrkB/CREB signaling pathway

Lin, Peipei; Wang, Chuang; Xu, Bing; Gao, Siyun; Guo, Jinghong; Zhao, Xin; Huang, Huihui; Zhang, Junfang; Chen, Xiaowei; Wang, Qinwen; Zhou, Wenhua

doi:10.1016/j.pbb.2014.03.003

Cited by 56 publications

(53 citation statements)

References 52 publications

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“…These studies further identified antidepressant efficacy of VGF-derived C-terminal peptides TLQP-62 (Thakker-Varia et al 2007) and AQEE-30 (Hunsberger et al 2007), and a requirement for VGF expression in the antidepressant efficacy of exercise (Hunsberger et al 2007). Subsequent reports have demonstrated a requirement for BDNF expression and BDNF/TrkB signaling in the antidepressant efficacy of TLQP-62 (Jiang et al 2017; Li et al 2017; Lin et al 2014). Prolonged antidepressant efficacy of TLQP-62, measured in the FST three and six days after a single intra-hippocampal infusion (Thakker-Varia et al 2007), or in the FST and TST, measured after 2 weeks of daily intra-hippocampal infusions (Lin et al 2014), could result at least in part from TLQP-62-mediated stimulation of hippocampal progenitor proliferation (Thakker-Varia et al 2014; Thakker-Varia et al 2007).…”

Section: Contributions Of the Secreted Protein And Peptide Precursor mentioning

confidence: 99%

“…Subsequent reports have demonstrated a requirement for BDNF expression and BDNF/TrkB signaling in the antidepressant efficacy of TLQP-62 (Jiang et al 2017; Li et al 2017; Lin et al 2014). Prolonged antidepressant efficacy of TLQP-62, measured in the FST three and six days after a single intra-hippocampal infusion (Thakker-Varia et al 2007), or in the FST and TST, measured after 2 weeks of daily intra-hippocampal infusions (Lin et al 2014), could result at least in part from TLQP-62-mediated stimulation of hippocampal progenitor proliferation (Thakker-Varia et al 2014; Thakker-Varia et al 2007). Rapid TLQP-62 antidepressant efficacy (30 min – 24 hr following intra-hippocampal delivery) in the FST (Jiang et al 2017; Lin et al 2014) has been shown, like the rapid-acting antidepressant ketamine, to require BDNF expression (Jiang et al 2017; Lin et al 2014), mTOR activity (rapamycin-sensitive) (Jiang et al 2017), and glutamate receptor activity (NBQX-sensitive) (Jiang et al 2017), suggesting a complementary, rapidly-initiated mechanism of action.…”

Section: Contributions Of the Secreted Protein And Peptide Precursor mentioning

confidence: 99%

“…Decreased VGF expression, resulting from germline or conditional Vgf gene ablation in mice, including targeted down-regulation in adult dorsal hippocampus (dHc), impacts depressive behavior, contextual fear, and hippocampal-dependent spatial memory (Bozdagi et al 2008; Hahm et al 1999; Hunsberger et al 2007; Jiang et al 2017; Lin et al 2015). VGF C-terminal peptides AQEE-30 and TLQP-62 (named by the four N-terminal amino acids and length) have antidepressant efficacy (Hunsberger et al 2007; Jiang et al 2017; Li et al 2017; Lin et al 2014; Thakker-Varia et al 2007), while TLQP-62 has also been shown to have pro-cognitive efficacy (Li et al 2017; Lin et al 2015). TLQP-62 functions via BDNF-dependent pathways (Bozdagi et al 2008; Jiang et al 2017; Lin et al 2014; Lin et al 2015), while the VGF 1–617 proprotein plays a critical role in growth factor, hormone, and neurotransmitter storage in dense core vesicles (DCVs) and regulated secretion (Fargali et al 2014; Stephens et al 2017).…”

Section: Introductionmentioning

confidence: 99%

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Role of a VGF/BDNF/TrkB Autoregulatory Feedback Loop in Rapid-Acting Antidepressant Efficacy

2018

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Members of the neurotrophin family and in particular brain-derived neurotrophic factor (BDNF) regulate the response to rapid- and slow-acting chemical antidepressants and voluntary exercise. Recent work suggests that rapid-acting antidepressants that modulate N-methyl-D-aspartate receptor (NMDA-R) signaling (e.g., ketamine and GLYX-13) require expression of VGF (non-acronymic), the BDNF-inducible secreted neuronal protein and peptide precursor, for efficacy. In addition, the VGF-derived C-terminal peptide TLQP-62 (named by its 4 N-terminal amino acids and length) has antidepressant efficacy following icv or intra-hippocampal administration, in the forced swim test (FST). Similar to ketamine, the rapid antidepressant actions of TLQP-62 require BDNF expression, mTOR activation (rapamycin-sensitive), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation (NBQX-sensitive) and are associated with GluR1 insertion. We review recent findings that identify a rapidly induced autoregulatory feedback loop, which likely plays a critical role in sustained efficacy of rapid-acting antidepressants, depression-like behavior, and cognition, and requires VGF, its C-terminal peptide TLQP-62, BDNF/TrkB signaling, the mTOR pathway, and AMPA receptor activation and insertion.

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Section: Contributions Of the Secreted Protein And Peptide Precursor mentioning

confidence: 99%

Section: Contributions Of the Secreted Protein And Peptide Precursor mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Role of a VGF/BDNF/TrkB Autoregulatory Feedback Loop in Rapid-Acting Antidepressant Efficacy

2018

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“…Major depressive disorder and chronic stress are characterized by downregulation of neurotrophins, such as BDNF in the hippocampus [20,21,22]. Similarly, VGF was found to be downregulated in the hippocampus in animal models of depression and human bipolar disorder, and previous studies have demonstrated that increasing levels of the VGF-derived C-terminal peptide TLQP-62 results in antidepressant-like behavioral effects in mice [23,24] in a manner that is dependent on BDNF/TrkB/CREB signaling [25]. Parallel to BDNF, TLQP-62’s behavioral actions are also mediated by the PI3K/Akt/mTOR pathway, supporting the notion that VGF is upstream of BDNF signaling [1,26].…”

Section: Introductionmentioning

confidence: 99%

Neuropeptide VGF Promotes Maturation of Hippocampal Dendrites That Is Reduced by Single Nucleotide Polymorphisms

Behnke

Cheedalla

Bhatt

et al. 2017

IJMS

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The neuropeptide VGF (non-acronymic) is induced by brain-derived neurotrophic factor and promotes hippocampal neurogenesis, as well as synaptic activity. However, morphological changes induced by VGF have not been elucidated. Developing hippocampal neurons were exposed to VGF through bath application or virus-mediated expression in vitro. VGF-derived peptide, TLQP-62, enhanced dendritic branching, and outgrowth. Furthermore, VGF increased dendritic spine density and the proportion of immature spines. Spine formation was associated with increased synaptic protein expression and co-localization of pre- and postsynaptic markers. Three non-synonymous single nucleotide polymorphisms (SNPs) were selected in human VGF gene. Transfection of N2a cells with plasmids containing these SNPs revealed no relative change in protein expression levels and normal protein size, except for a truncated protein from the premature stop codon, E525X. All three SNPs resulted in a lower proportion of N2a cells bearing neurites relative to wild-type VGF. Furthermore, all three mutations reduced the total length of dendrites in developing hippocampal neurons. Taken together, our results suggest VGF enhances dendritic maturation and that these effects can be altered by common mutations in the VGF gene. The findings may have implications for people suffering from psychiatric disease or other conditions who may have altered VGF levels.

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“…Unfortunately, in this study, we failed to detect, by MS analysis, peptides containing the TLQP and GGGE sequences probably due to the low intensity of their ions. TLQP peptides were first identified in the rat brain (Trani et al, 2002) but despite their role in neuronal circuits (Thakker-Varia et al, 2007, 2010; Lin et al, 2014), they have never been identified by MS analysis, suggesting particular adversities to reveal them with this technique. However, the high levels of these peptides revealed by ELISA in the hypothalamus and hippocampus are in line with their known bioactivity in these areas (Hahm et al, 1999, 2002; Jethwa and Ebling, 2008).…”

Section: Discussionmentioning

confidence: 99%

Profiles of VGF Peptides in the Rat Brain and Their Modulations after Phencyclidine Treatment

Noli

Sanna

Brancia

et al. 2017

Front. Cell. Neurosci.

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From the VGF precursor protein originate several low molecular weight peptides, whose distribution in the brain and blood circulation is not entirely known. Among the VGF peptides, those containing the N-terminus portion were altered in the cerebro-spinal fluid (CSF) and hypothalamus of schizophrenia patients. “Hence, we aimed to better investigate the involvement of the VGF peptides in schizophrenia by studying their localization in the brain regions relevant for the disease, and revealing their possible modulations in response to certain neuronal alterations occurring in schizophrenia”. We produced antibodies against different VGF peptides encompassing the N-terminus, but also C-terminus-, TLQP-, GGGE- peptide sequences, and the so named NERP-3 and -4. These antibodies were used to carry out specific ELISA and immunolocalization studies while mass spectrometry (MS) analysis was also performed to recognize the intact brain VGF fragments. We used a schizophrenia rat model, in which alterations in the prepulse inhibition (PPI) of the acoustic startle response occurred after PCP treatment. In normal rats, all the VGF peptides studied were distributed in the brain areas examined including hypothalamus, prefrontal cortex, hippocampus, accumbens and amygdaloid nuclei and also in the plasma. By liquid chromatography-high resolution mass, we identified different intact VGF peptide fragments, including those encompassing the N-terminus and the NERPs. PCP treatment caused behavioral changes that closely mimic schizophrenia, estimated by us as a disruption of PPI of the acoustic startle response. The PCP treatment also induced selective changes in the VGF peptide levels within certain brain areas. Indeed, an increase in VGF C-terminus and TLQP peptides was revealed in the prefrontal cortex (p < 0.01) where they were localized within parvoalbumin and tyrosine hydroxylase (TH) containing neurons, respectively. Conversely, in the nucleus accumbens, PCP treatment produced a down-regulation in the levels of VGF C-terminus-, N-terminus- and GGGE- peptides (p < 0.01), expressed in GABAergic- (C-terminus/GGGE) and somatostatin- (N-terminus) neurons. These results confirm that VGF peptides are widely distributed in the brain and modulated in specific areas involved in schizophrenia.

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The VGF-derived peptide TLQP62 produces antidepressant-like effects in mice via the BDNF/TrkB/CREB signaling pathway

Cited by 56 publications

References 52 publications

Role of a VGF/BDNF/TrkB Autoregulatory Feedback Loop in Rapid-Acting Antidepressant Efficacy

Role of a VGF/BDNF/TrkB Autoregulatory Feedback Loop in Rapid-Acting Antidepressant Efficacy

Neuropeptide VGF Promotes Maturation of Hippocampal Dendrites That Is Reduced by Single Nucleotide Polymorphisms

Profiles of VGF Peptides in the Rat Brain and Their Modulations after Phencyclidine Treatment

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