Regulation of Dendritic Development by BDNF Requires Activation of CRTC1 by Glutamate

Abstract

Dendritic growth is essential for the establishment of a functional nervous system. Among extrinsic signals that control dendritic development, substantial evidence indicates that BDNF regulates dendritic morphology. However, little is known about the underlying mechanisms by which BDNF controls dendritic growth. In this study, we show that the MAPK signaling pathway and the transcription factor cAMP response elementbinding protein (CREB) mediate the effects of BDNF on dendritic length and complexity. However, phosphorylation of CREB alone is not sufficient for the stimulation of dendritic growth by BDNF. Thus, using a mutant form of CREB unable to bind CREB-regulated transcription coactivator (CRTC1), we demonstrate that this effect also requires a functional interaction between CREB and CRTC1. Moreover, inhibition of CRTC1 expression by shRNA-mediated knockdown abolished BDNF-induced dendritic growth of cortical neurons. Interestingly, we found that nuclear translocation of CRTC1 results from activation of NMDA receptors by glutamate, a process that is essential for the effects of BDNF on dendritic development. Together, these data identify a previously unrecognized mechanism by which CREB and the coactivator CRTC1 mediate the effects of BDNF on dendritic growth.

Cell class-specific regulation of neocortical dendrite and spine growth by AMPA receptor splice and editing variants

“…NMDARs are known to influence the differentiation of pyramidal cells. For example, blocking NMDARs until P21 in vivo results in prefrontal cortical pyramidal cells with smaller dendritic trees (Wedzony et al, 2005), blocking NMDARs in vitro abolishes the growth-promoting effect of BDNF (Finsterwald et al, 2010), and, in the absence of NMDARs, spiny stellate neurons fail to orient their dendrites towards the barrels (Espinosa et al, 2009;Iwasato et al, 2000). Moreover, hippocampal pyramidal neurons and granule cells lacking the NMDAR subunit GluNR2B have reduced spine density but display dendritic trees similar in length and branching to wildtype neurons, and the same has been observed for barrel cortex spiny stellate cells at P21 (Espinosa et al, 2009 developmental analysis shows no differences in dendritic length and branching between wild-type and single-cell GluN2B knockout spiny stellate neurons (Espinosa et al, 2009).…”

More Than Just an OFF-Switch: The Essential Role of Protein Dephosphorylation in the Modulation of BDNF Signaling Events

“…Calcineurin, a calcium sensing phosphatase, directly dephosphorylates CRTC proteins. BDNF signaling induces robust and sustained phosphorylation of CREB, but cannot elicit nuclear translocation of CRTC1 (38). In similar experiments conducted in hypothalamic neurons, where CRTC2 is the major isoform expressed, BDNF signaling did not elicit CRTC2 translocation to the nucleus, while cAMPelevating drugs or drugs that elevate intracellular calcium did (41).…”

“…So, what neuronal mechanisms mediate calcineurin-dependent dephosphorylation of CRTC protein? Neuronal activity via calcium-permeable glutamate ion channels not only phosphorylates CREB, but also triggers the calcineurin-dependent dephosphorylation of CRTC1 in cortical neurons and of CRTC2 in hypothalamic neurons that is necessary to activate CREB-mediated transcription (38,41). Consequently, they reside in the cytoplasm via sequestration by the 14-3-3 family of proteins.…”

“…For instance, CRTC1 null mice decrease BDNF expression in the prefrontal cortex and hippocampus down to 40 % of wildtype levels, suggesting additional mechanisms of regulation and/ or compensatory mechanisms (37). Knockdown of CRTC1, the major isoform in the limbic brain is sufficient to prevent BDNF-induced structural plasticity such as dendritic and axonal arborization, as well as physiological features like long-term potentiation that also depends on BDNF/TrkB signaling (38,39). Because the transcriptional activity of CREB downstream of BDNF depends on CRTC1 and perhaps other CRTC isoforms, it is now interesting to describe how CRTC1 function is regulated.…”

Ankyrin Repeat-Rich Membrane Spanning Protein (Kidins220) Is Required for Neurotrophin and Ephrin Receptor-Dependent Dendrite Development

“…For example, soluble factors, including brain-derived neurotrophic factor (BDNF) and other neurotrophins, as well as transmembrane ligands like ephrinB, regulate dendritic morphogenesis through their cell surface receptors in coordination with the signaling pathways triggered by neuronal activity (McAllister et al, 1995;Hoogenraad et al, 2005;Konur and Ghosh, 2005). These cell surface receptors regulate the growth or maintenance of dendrites through modulation of Ras-MEK-MAPK and PI3K (phosphoinositide-3-kinase)-Akt-mTOR (mammalian target of rapamycin)-regulated protein translation pathways, CREBdependent gene transcription, and small Rho GTPase-mediated cytoskeletal reorganization (Dijkhuizen and Ghosh, 2005;Govek et al, 2005;Jaworski et al, 2005;Cheung et al, 2007;Finsterwald et al, 2010;Kwon et al, 2011). Nonetheless, the molecular mechanisms that relay the signals from the cell surface receptors to intracellular effectors during dendrite development remain unclear.…”