AMPA Receptor-Mediated, Calcium-Dependent CREB Phosphorylation in a Subpopulation of Auditory Neurons Surviving Activity Deprivation

Abstract

Although dependence on afferent synaptic activity has been shown for central neurons in every sensory system, the mechanisms of afferent maintenance of target sensory neurons are not understood. Neurons in the cochlear nucleus (CN) require afferent activity for maintenance and survival. One of the earliest changes seen after activity deprivation is an increase in intracellular calcium that leads to the death of 30% of the neuronal population. Sixty minutes after deafferentation, the surviving neurons show increased phosphorylation of the transcription factor calcium/cAMP response element-binding protein (CREB). CREB phosphorylation in activity-deprived CN neurons is dependent on increased intracellular calcium resulting from influx through AMPA receptors and is mediated by calcium/calmodulin-dependent kinases and protein kinase A. We conclude that in CN neurons, the deafferentation-induced increase in calcium activates at least two kinase pathways that phosphorylate CREB in surviving neurons. We hypothesize that this phosphorylation results in the transcription of genes containing the calcium/cAMP response element within their promoter regions, and these genes code for proteins that allow the neurons to compensate for their hypercalcemic, activity-deprived state.

Deafferentation-Induced Activation of NFAT (Nuclear Factor of Activated T-Cells) in Cochlear Nucleus Neurons during a Developmental Critical Period: A Role for NFATc4-Dependent Apoptosis in the CNS

“…P7, P14, and P21 C57BL mice (Harlan, Indianapolis, IN) were used for these studies, and procedures were approved by the Institutional Animal Care and Use Committee of the University of Minnesota. For all experiments, mice at these three ages were unilaterally deafferented by cochlea ablation (Mostafapour et al, 2000;Zirpel et al, 2000) while anesthetized with isoflurane. Ages stated for data are the age at which the surgery was performed.…”

“…After deafferentation of chick NM neurons, a rapid rise in intracellular calcium concentration ([Ca 2ϩ ] i ) (Zirpel et al, 1995) activates the transcription factor cAMP response elementbinding protein (CREB), leading to transcription of prosurvival proteins (Zirpel et al, 2000). All of the NM neurons show an increase in [Ca 2ϩ ] i , but only a subpopulation activate CREB and survive deafferentation.…”

Primary innervation of the avian and mammalian cochlear nucleus

“…Activity-dependent activation of Group I mGluRs (which includes two related proteins, mGluRs 1 and 5) releases Ca 2+ from intracellular stores in chick NM neurons by activating phospholipase C, which generates IP 3 [231]. This mGluR-mediated effect on calcium homeostasis develops in parallel with synaptic activity in NM [229] and has been shown to be necessary for the survival of many NM neurons [230,231]. It has recently been found that zinc is localized in chick cochlear nerve endbulbs (Fig.…”

Screening of the Human Kinome Identifies MSK1/2-CREB1 as an Essential Pathway Mediating Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication during Primary Infection

“…CREB1, through binding to a conserved DNA sequence called the cAMP-responsive element (CRE), acts downstream of a wide variety of signals in cells to mediate many functions, including immune function, memory, metabolism, and cell survival (24)(25)(26)(27)(28). CREB1 has been implicated in regulating viral gene expression of a number of viruses, including hepatitis B virus (HBV) (29), herpes simplex virus 1 (HSV-1) (30), human cytomegalovirus (HCMV) (31), and human T-cell leukemia virus (HTLV) (32,33).…”