Mechanisms Of Neurotransmissionmediated Dendrite Growth

It is not yet clear how neuronal transmission translates into the activity-dependent changes in dendrite growth and synaptogenesis described above. One certain component of this pathway, however, is elevation of intracellular Ca2+ 67,68. At glutamatergic synapses, the primary source for extracellular Ca2+ entry into dendrites is through NMDA receptors and L-type voltage-sensitive Ca2+ channels (VSCCs)30,67,69. Ca2+ can also be released from intracellular stores, including inositol-1,4,5-triphosphate (Ins(1,4,5)P3)-ryanodine-sensitive stores, and Ca2+-induced release from the endoplasmic reticulum. Imaging Ca2+ signals in developing neurons has detected spontaneous transient elevations that are either spatially restricted to short regions of dendrites, or globally distributed throughout the arbor. Attempts to correlate these spontaneous events to filopodial motility have yielded varying results that may be due to the neuronal maturational stage, cell type, or the precise spatial and temporal characteristics of the Ca2+ transients observed. Exposing acute neonatal rat cortical slices to Ca2+-free media increased filopodia length and density, suggesting that entry of extracellular Ca2+ contributes to stabilization13. In developing RGCs, Ca2+ transients attributed to local release from intracellular stores have been implicated in filopodia stabilization, while blocking release from these stores promotes branch retraction70,71. In immature hippocampal neurons, local Ca2+ transients in filopodia and shafts could be well correlated to filopodial motility71. Ca2+ levels are low in dendritic shafts when filopodia first extend, local Ca2+ transient become more frequent as filopodia begin growing, and when the occurrence of Ca2+ transient is high filopodia become immobile. Reducing local Ca2+ transients increases filopodial growth, while uncaging Ca2+ within dendrites reduced filopodial motility. These findings suggest that low levels of Ca2+ promote outgrowth and high levels stabilize filopodial. Ca2+ elevation associated with NMDA receptor activation and depolarization increases dendrite growth and has been shown to require activation and further Ca2+ through VSCCs55. Ca2+ entry through VSCCs is also necessary in developing ferret cortical slices for neurotrophin-induced dendrite growth of layer 4 pyramidal neurons52. One model to emerge from these studies involves glutamatergic innervation-induced entry of Ca2+ through NMDA receptors and local depolarization-induced activation and Ca2+ flux through L-type VSCCs. Entry of extracellular Ca2+ triggers further local release from intracellular stores, and this spatially restricted Ca2+ transients leads to stabilization of filopodia receiving appropriate innervation. Local filopodia stabilization is a necessary step in dendrite growth because it prevents retraction, but allows further subsequent extension to create a longer and persistent dendritic branch.

Ca2+ appears to affect growth through two mechanisms: rapid action affecting local motility, and slower global effects on growth72. Little is known of the specific effectors of Ca2+ that mediate these different effects, but downstream targets of Ca2+ influx effecting dendrite plasticity are emerging, including the Ca2+/calmodulin-dependent protein kinases CaMKII and CaMKIV, and mitogen-activated protein kinase (MAPK)67,68,73. Both CaMKII and CaMKIV are developmentally regulated in neurons with maximal levels during the maximal period of dendrite growth68. In vivo studies in Xenopus tectum find that inhibition of CaMKII increases dendrite growth74,75, and expression of constitutively active CaMKII restricts growth74, suggesting that CaMKII may play a role in dendritic branch stabilization and potentially contribute to rapid Ca2+ effects. Supporting the connection between synaptogenesis and filopodia stabilization, expression of constitutively active CaMKII in immature tectal neurons promotes both glutamatergic synapse maturation (increased AMPA receptor expression) and dendrite stabilization. Overexpression of CaMKIV by itself did not promote growth, but greatly enhanced the growth-promoting effects of depolarization-induced Ca2+ influx68. The effects of CaMKIV on dendrite growth are likely mediated by changes in gene expression since CaMKIV is targeted to the nucleus and has been shown to interact with the transcription factor cyclic-AMP-responsive-element binding protein (CREB). Growth induced by influx of Ca2+ through VSCCs and activation of CaMKIV is blocked by expression of dominant negative CREB, demonstrating that CREB activation is a required downstream mediator of Ca2+-dependent dendritic growth68. It remains unclear, however, how CREB activation leads to changes in dendrite growth. One transcriptional target of CREB is BDNF, which has been shown to regulate dendritic growth in cortical and cerebellar neurons5,9,52. Recently, another member of this pathway has been discovered called CREST76. CREST is a Ca2+-responsive transactivator that is developmentally expressed in cortex during periods of dendrite growth. CREST

binds to the CREB-binding protein (CBP), and Ca2+ influx through NMDA receptors and VSCCs activate CREST-mediated transcription. Trangenic mice expressing mutated CREST express reduced dendrite growth and branching in hippocampal neurons, and expression of mutated CREST in cultured hippocampal neurons blocks depolarization-induced dendrite growth. Transcriptional regulation mediated through CaMKIV, CREB, and CREST may mediate the slow activating long-lasting effects of activity on growth.

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