Definition of a Bidirectional Activity-Dependent Pathway Involving BDNF and Narp

Abstract

Summary One of the cardinal features of neural development and adult plasticity is the contribution of activity-dependent signaling pathways. However, the interrelationships between different activity-dependent genes are not well understood. The immediate early gene, neuronal activity-regulated pentraxin (NPTX2 or Narp), encodes a protein that has been associated with excitatory synaptogenesis, AMPA receptor aggregation and the onset of critical periods. Here we show that Narp is a direct transcriptional target of Brain-derived neurotrophic factor (BDNF), another highly regulated activity-dependent gene involved in synaptic plasticity. Unexpectedly, Narp is bi-directionally regulated by BDNF. Acute BDNF withdrawal results in downregulation of Narp, whereas transcription of Narp is greatly enhanced by BDNF. Furthermore, our results show that BDNF directly regulates Narp to mediate glutamatergic transmission and mossy fiber plasticity. Hence, Narp serves as a significant epistatic target of BDNF to regulate synaptic plasticity during periods of dynamic activity.

TrkB Signaling Influences Gene Expression in Cortistatin-Expressing Interneurons

“…1C). For example, we observed altered expression of neuronal pentraxin II (Nptx2; log2FC ϭ 1.26, p ϭ 3.60 ϫ 10 Ϫ5 ), which encodes a synaptic protein implicated in excitatory synapse formation and neural plasticity (Gu et al, 2013) that is bidirectionally regulated by BDNF in hippocampal neurons both in vitro and in vivo (Mariga et al, 2015). Our dataset also shows increases in cAMP-responsive element Binding Protein 3 Like 1, which is necessary and sufficient to activate Nptx2 transcription after BDNF treatment (Mariga et al, 2015).…”

The Role of Neuronal Pentraxin 2 (NP2) in Regulating Glutamatergic Signaling and Neuropathology

“…While the mechanism proposed herein has its foundation in the research, there are many gaps that need to be addressed. We know that NP2 is upregulated in response to synaptic activity and BDNF (Tsui et al, 1996;Mariga et al, 2015), but we do not know what other downstream effects may be occurring. Furthermore, almost all research concerning NP2 has been conducted on neurons.…”

“…NP1 and NP2 exist as CRP 20-30% 1 Not known 24% 3 SAP 20-30% 1 Not known 26% 3 Apexin Not known 88% 1 Not known NPR 49% 2 48% 2 Not known NP1 -54% 1 45% 3 NP2 54% 1 -94% 3 1 Hsu and Perin (1995), 2 Dodds et al (1997) and 3 Tsui et al (1996). (Xu et al, 2003;Mariga et al, 2015).…”

“…(1) Pentameric NP2 is released from the pre-synaptic cell in response to neuronal activity/seizure (Tsui et al, 1996) or brain-derived neurotrophic factor (BDNF) induction (Mariga et al, 2015). (2) NP2 makes its way to the post-synaptic membrane, possibly facilitated via perineuronal nets (van't Spijker and Kwok, 2017).…”

“…As an IEG, NP2 is upregulated in response to synaptic activity (Tsui et al, 1996). Mariga et al (2015) found that NP2 has a bidirectional relationship with brain-derived neurotrophic factor (BDNF), wherein BDNF is able to induce NP2 expression even in the absence of neuronal activity. Once NP2 is released into the synapse, it can accumulate on the pre-or post-synaptic membrane surface with the help of perineuronal nets (PNN's) via a calcium-dependent binding (Chang et al, 2010;van't Spijker and Kwok, 2017).…”