Reciprocal Regulation of Presynaptic and Postsynaptic Proteins in Bipolar Spiral Ganglion Neurons by Neurotrophins

Flores‐Otero, Jacqueline; Xue, Hui Zhong; Davis, Robin L.

doi:10.1523/jneurosci.3219-07.2007

Cited by 75 publications

(94 citation statements)

References 62 publications

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“…In previous studies, neurons extended processes to HCs in vitro after prior removal of SGNs (MartinezMonedero et al 2006;Flores-Otero et al 2007;Martinez-Monedero et al 2008). In the present study we evaluated the contacts generated between cultured SGNs and denervated HCs and found PSD-95 immunopositive puncta directly facing the HC ribbons.…”

Section: Introductionmentioning

confidence: 59%

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Regenerated Synapses Between Postnatal Hair Cells and Auditory Neurons

Tong

Brugeaud

Edge

2013

JARO

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Regeneration of synaptic connections between hair cells and spiral ganglion neurons would be required to restore hearing after neural loss. Here we demonstrate by immunohistochemistry the appearance of afferent-like cochlear synapses in vitro after co-culture of de-afferented organ of Corti with spiral ganglion neurons from newborn mice. The glutamatergic synaptic complexes at the ribbon synapse of the inner hair cell contain markers for presynaptic ribbons and postsynaptic densities. We found postsynaptic density protein PSD-95 at the contacts between hair cells and spiral ganglion neurons in newly formed synapses in vitro. The postsynaptic proteins were directly facing the CtBP2-positive presynaptic ribbons of the hair cells. BDNF and NT-3 promoted afferent synaptogenesis in vitro. Direct juxtaposition of the postsynaptic densities with the components of the preexisting ribbon synapse indicated that growing fibers recognized components of the presynaptic sites. Initiation of cochlear synaptogenesis appeared to be influenced by glutamate release from the hair cell ribbons at the presynaptic site since the synaptic regeneration was impaired in glutamate vesicular transporter 3 mutant mice. These insights into cochlear synaptogenesis could be relevant to regenerative approaches for neural loss in the cochlea.

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Section: Introductionmentioning

confidence: 59%

“…In previous studies, neurons extended processes to HCs in vitro and expressed synaptic markers (MartinezMonedero et al 2006;Flores-Otero et al 2007;Martinez-Monedero et al 2008). However, postsynaptic structures of the auditory HC synapse were not assessed.…”

Section: Discussionmentioning

confidence: 87%

Regenerated Synapses Between Postnatal Hair Cells and Auditory Neurons

Tong

Brugeaud

Edge

2013

JARO

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“…For example, they have been shown to regulate transmitter release, synaptic size and stability, and to modulate shortand long-term synaptic plasticity (56)(57)(58)(59). Although neurons have long been viewed as the primary source of BDNF in the central nervous system, recent studies have reported BDNF expression in both oligodendrocytes and astrocytes (60)(61)(62).…”

Section: Discussionmentioning

confidence: 99%

Nonneuronal cells regulate synapse formation in the vestibular sensory epithelium via erbB-dependent BDNF expression

Gómez-Casati

Murtie

Río

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Synaptogenesis is typically viewed as a process involving only the pre-and postsynaptic neurons, but recent studies suggest that astrocytes are also involved. For example, studies show that astrocytes release thrombospondins, which interact with neuronal gabapentin receptors that, upon activation, induce the formation of excitatory synapses in the central nervous system (1-3). Other studies have shown that complexes of cholesterol and apolipoprotein E-containing lipoproteins released by astrocytes are required for synaptogenesis by purified retinal ganglion cells (4). Although these studies suggest that glia may regulate synapse formation, a number of key questions remain unanswered: (i) Are astrocytes the only glia with synaptogenic activity? (ii) Are thombospondin and cholesterol/ApoE complexes the only glial-derived synaptogenic factors? (iii) Do glia produce synaptogenic factors on their own or in response to other signals? And (iv) what are the functional consequences of disruption of glial-induced synaptogenesis? Our studies on neuron-glia interactions in the vestibular system answer these questions.The vestibular organs provide information about head position and thus contribute to the maintenance of balance and posture. Linear acceleration is transformed into neural signals by mechanotransducing hair cells in sensory epithelia, called maculae, in the orthogonally oriented saccule and utricle. These hair cells synapse on primary sensory neurons that send the information to the brainstem. Vestibular hair cells and their associated sensory nerve terminals are surrounded by nonneuronal cells, called supporting cells (SCs). These SCs express glial markers such as vimentin (5), S100 (6), glutamate-aspartate transporter (7), lowaffinity neurotrophin receptor p75 (8), glial fibrillary acidic protein (GFAP) (9), and proteolipid protein (PLP) (10). They surround synaptic contacts, as astrocytes and perisynaptic Schwann cells do at central and neuromuscular synapses, respectively. Moreover, during development, these nonneuronal cells are precursors for hair cells (11,12), as radial glia are to neurons. Based on these similarities, we hypothesized that interactions of SCs with vestibular neurons and hair cells could be important for the vestibular system, and that the communication between neuronal and nonneuronal cells of the vestibular sensory epithelia could be mediated by some of the same molecules that mediate neuron-glia interactions elsewhere in the nervous system.The growth factor neuregulin 1 (NRG1) and its receptors, the erbB family of tyrosine kinase receptors, have emerged as key mediators of neuron-glia interactions throughout the nervous system (13,14). NRGs are members of the EGF family of growth factors and signal through erbB2, erbB3, and erbB4 (14, 15). NRG1 is expressed primarily by neurons, including many peripheral sensory neurons (16), whereas glial cells express erbB receptors (14,(17)(18)(19). The NRG1/erbB signaling pathway is important for axon-Schwann cell interactions that regulate myeli...

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“…1 Stage 3 (26 days = 5 DIV; 31 days = 10 DIV), before being fixed and processed for immunocytochemistry. In an additional set of experiments, cochlear explants were denervated to dissect the hair cells from the neural tissue in the explants, using microdissection techniques previously described [38,39]. In these experiments, the hair cells alone were cocultured with Y27632-treated NS for 10 DIV to investigate the formation of preand postsynaptic terminals between stem cells and hair cells.…”

Section: Early Postnatal Cochlear Explant Dissections and Coculturesmentioning

confidence: 99%

An In Vitro Model of Developmental Synaptogenesis Using Cocultures of Human Neural Progenitors and Cochlear Explants

Nayagam

Edge²,

Needham³

et al. 2013

Stem Cells and Development

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In mammals, the sensory hair cells and auditory neurons do not spontaneously regenerate and their loss results in permanent hearing impairment. Stem cell therapy is one emerging strategy that is being investigated to overcome the loss of sensory cells after hearing loss. To successfully replace auditory neurons, stem cell-derived neurons must be electrically active, capable of organized outgrowth of processes, and of making functional connections with appropriate tissues. We have developed an in vitro assay to test these parameters using cocultures of developing cochlear explants together with neural progenitors derived from human embryonic stem cells (hESCs). We found that these neural progenitors are electrically active and extend their neurites toward the sensory hair cells in cochlear explants. Importantly, this neurite extension was found to be significantly greater when neural progenitors were predifferentiated toward a neural crest-like lineage. When grown in coculture with hair cells only (denervated cochlear explants), stem cell-derived processes were capable of locating and growing along the hair cell rows in an en passant-like manner. Many presynaptic terminals (synapsin 1-positive) were observed between hair cells and stem cell-derived processes in vitro. These results suggest that differentiated hESC-derived neural progenitors may be useful for developing therapies directed at auditory nerve replacement, including complementing emerging hair cell regeneration therapies.

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Reciprocal Regulation of Presynaptic and Postsynaptic Proteins in Bipolar Spiral Ganglion Neurons by Neurotrophins

Cited by 75 publications

References 62 publications

Regenerated Synapses Between Postnatal Hair Cells and Auditory Neurons

Regenerated Synapses Between Postnatal Hair Cells and Auditory Neurons

Nonneuronal cells regulate synapse formation in the vestibular sensory epithelium via erbB-dependent BDNF expression

An In Vitro Model of Developmental Synaptogenesis Using Cocultures of Human Neural Progenitors and Cochlear Explants

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