Abstract
The release of neuropeptides from dense core vesicles (DCVs) modulates neuronal activity and plays a critical role in cognitive function and emotion. The granin family is considered a master regulator of DCV biogenesis and the release of DCV cargo molecules. The expression of the VGF protein (nonacronymic), a secreted neuropeptide precursor that also belongs to the extended granin family, has been previously shown to be induced in the brain by hippocampus-dependent learning, and its downregulation is mechanistically linked to neurodegenerative diseases such as Alzheimer’s disease and other mood disorders. Currently, whether changes in translational efficiency of Vgf and other granin mRNAs may be associated and regulated with learning associated neural activity remains largely unknown. Here, we show that either contextual fear memory training or the administration of TLQP-62, a peptide derived from the C-terminal region of the VGF precursor, acutely increases the translation of VGF and other granin proteins, such as CgB and Scg2, via an mTOR-dependent signaling pathway in the absence of measurable increases in mRNA expression. Luciferase-based reporter assays confirmed that the 3′-untranslated region (3′UTR) of the Vgf mRNA represses VGF translation. Consistently, the truncation of the endogenous Vgf mRNA 3′UTR results in substantial increases in VGF protein expression both in cultured primary neurons and in brain tissues from knock in mice expressing a 3′UTR-truncation mutant encoded by the modified Vgf gene. Importantly, Vgf 3′UTR-truncated mice exhibit enhanced memory performance and reduced anxiety- and depression-like behaviors. Our results therefore reveal a rapid, transcription-independent induction of VGF and other granin proteins after learning that are triggered by the VGF-derived peptide TLQP-62. Our findings suggest that the rapid, positive feedforward increase in the synthesis of granin family proteins might be a general mechanism to replenish DCV cargo molecules that have been released in response to neuronal activation and is crucial for memory function and mood stability.
Highlights
Neuropeptides play critical roles in the modulation of neural activity and synaptic plasticity, which are required for memory formation and emotional behavior
In the Vgf 3′UTRtruncated female mice, we found no significant difference in open field test and Forced swim test (FST) performance, there is a trend of increased time in the center area of a novel arena (Supplemental Fig. 5A, B)
In the current study, we identified a posttranscriptional mechanism that acutely regulates the translation of VGF and other granin proteins immediately after contextual fear conditioning or TLQP-62 peptide treatment
Summary
Neuropeptides play critical roles in the modulation of neural activity and synaptic plasticity, which are required for memory formation and emotional behavior. Proteins of the extended granin family, including VGF (nonacronymic), chromogranin A (CgA), chromogranin B (CgB), secretogranin 2 (Scg2), and secretogranin 3 (Scg3), are the major components of DCVs that are known to play critical roles in DCV biogenesis, sorting, and regulated secretion [6]. In addition to contributions to DCV biogenesis, granin proteins and their processed peptides are released into the extracellular space in a regulated manner, where they function mouse hippocampal neurons are described in the Supplemental Methods. In recent studies, reduced cerebrospinal fluid (CSF) levels or brain expression of VGF, Scg, CgB, and CgA proteins have been reported in patients with Alzheimer’s disease (AD), with an scrambled SC-62 peptide for 10 min and harvested in ice-cold protein lysis buffer.
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