Brain-Derived Neurotrophic Factor-Induced Gene Expression Reveals Novel Actions of VGF in Hippocampal Synaptic Plasticity

Abstract

Synaptic strengthening induced by brain-derived neurotrophic factor (BDNF) is associated with learning and is coupled to transcriptional activation. However, identification of the spectrum of genes associated with BDNF-induced synaptic plasticity and the correlation of expression with learning paradigms in vivo has not yet been studied. Transcriptional analysis of BDNF-induced synaptic strengthening in cultured hippocampal neurons revealed increased expression of the immediate early genes (IEGs), c-fos, early growth response gene 1 (EGR1), activity-regulated cytoskeletal-associated protein (Arc) at 20 min, and the secreted peptide VGF (non-acronymic) protein precursor at 3 hr. The induced genes served as prototypes to decipher mechanisms of both BDNF-induced transcription and plasticity. BDNF-mediated gene expression was tyrosine kinase B and mitogen-activated protein kinase-dependent, as demonstrated by pharmacological studies. Single-cell transcriptional analysis of Arc after whole-cell patch-clamp recordings indicated that increased gene expression correlated with enhancement of synaptic transmission by BDNF. Increased expression in vitro predicted elevations in vivo: VGF and the IEGs increased after trace eyeblink conditioning, a hippocampal-dependent learning paradigm. VGF protein was also upregulated by BDNF treatment and was expressed in a punctate manner in dissociated hippocampal neurons. Collectively, these findings suggested that the VGF neuropeptides may regulate synaptic function. We found a novel function for VGF by applying VGF peptides to neurons. C-terminal VGF peptides acutely increased synaptic charge in a dose-dependent manner, whereas N-terminal peptide had no effect. These observations indicate that gene profiling in vitro can reveal new mechanisms of synaptic strengthening associated with learning and memory.

The Neuropeptide VGF Produces Antidepressant-Like Behavioral Effects and Enhances Proliferation in the Hippocampus

“…Among the many classes of genes induced by BDNF, our studies reveal that synaptic vesicle proteins and neuropeptides are important regulators of hippocampal function (Thakker-Varia et al, 2001;Alder et al, 2003Alder et al, , 2005Ring et al, 2006). We recently discovered a role for the neuropeptide VGF in mediating synaptic activity of hippocampal cells (Alder et al, 2003). In this report, we show that the neuropeptide VGF is upregulated by both BDNF and 5-HT treatment and that VGF protein in the hippocampus is reduced in animals subjected to behavioral models of depression.…”

“…BDNF may mediate its many actions through the expression of downstream molecules. We successfully used transcriptional profiling after neurotrophin treatment to identify novel roles for genes in neuronal function (Thakker-Varia et al, 2001;Alder et al, 2003). Among the many classes of genes induced by BDNF, our studies reveal that synaptic vesicle proteins and neuropeptides are important regulators of hippocampal function (Thakker-Varia et al, 2001;Alder et al, 2003Alder et al, , 2005Ring et al, 2006).…”

Chronic intracerebroventricular injection of TLQP-21 prevents high fat diet induced weight gain in fast weight-gaining mice

“…Upon processing by the neuroendocrine-specific prohormone convertases PC1/3 and PC2, VGF may yield a number of peptides that are stored in dense core granules and secreted through regulated pathways [66]. Up to now, six VGFpeptides were shown to modulate with a remarkable peptide-specific selectivity, a diverse range of biological functions such as synaptic plasticity, apoptosis, sexual antidepressant-like behavior and inflammatory pain [2,7,10,11,35,37,58,63,64,65,70].…”

VGF, a New Player in Antidepressant Action?

“…Although one group was identifying downstream targets of exercise, and the other was focused on gene expression changes that were common following elevation of two putative mediators of antidepressant efficacy, the identification of VGF by both suggests a point of convergence between exercise and antidepressant signaling. Note that VGF is widely expressed in neurons in the brain and is involved in maintaining organismal energy balance, as well as in mediating hippocampal synaptic activity (19)(20)(21).…”