Dopamine Increases Hair-Cell Mechanotransduction Currents
Cecilia Toro, Josef G. Trapani, Itallia Pacentine, Reo Maeda, Lavinia Sheets, et al.
(see pages 16494–16503)
GABAergic, cholinergic, and dopaminergic efferents from the superior olive and surrounding areas modulate cochlear responses to sound, and thus contribute to sound localization, selective attention, adaptation, and protection from sound-induced damage. While the role of cholinergic innervation in these processes is fairly well understood, the role of dopaminergic modulation is unclear. Indeed, previous studies have reported contradictory results, showing, for example, that activating specific dopamine-receptor subtypes can either increase or decrease cochlear responses. The expression of different receptor subtypes by different cochlear cells, the lack of specific agonists and antagonists for each receptor type, and the inaccessibly of the cochlea to single-unit recording have hindered attempts to unravel the effects of dopamine on cochlear neurotransmission.
To overcome these difficulties, Toro et al. turned to the lateral line of zebrafish to gain insight into how dopamine influences hair-cell function. Dopamine efferents terminating in lateral-line neuromasts did not appear to make synaptic contacts with hair cells, afferent fibers, or other efferent fibers. Nonetheless, dopamine D1b receptors (D1bRs)—the only dopamine receptors detected in neuromasts—were localized to the synaptic ribbon of hair cells. Moreover, a D1R antagonist reduced calcium influx through hair-cell mechanotransduction channels and reduced microphonic potentials evoked by mechanical stimulation of hair cells. Conversely, a D1R agonist increased stimulation-induced calcium influx and microphonic potentials. Finally, blocking CaV1.3 calcium channels (which mediate calcium influx at ribbon synapses) occluded the effect of the D1R agonist.
Together, these data suggest that D1bRs in lateral-line hair cells are tonically activated by dopamine released in a paracrine fashion (rather than at synapses), and that this activation enhances calcium influx through mechanotransduction channels. Notably, D1bRs were also localized to ribbon-synapse active zones in the zebrafish inner ear and were not directly apposed by efferent fibers, suggesting dopamine's effect on auditory hair cells may parallel its role in the lateral line. Like in the mammalian cochlea, however, multiple dopamine receptor subtypes were expressed in zebrafish ears, indicating the effect of dopamine on auditory function is likely to be more complicated. Elucidating these effects may help identify ways to protect hair cells from acoustic damage and improve sound discrimination in the hearing impaired.
Neuregulin-2 Promotes Synaptogenesis in Two Ways
Kyu-Hee Lee, Hyunsu Lee, Che Ho Yang, Jeong-Soon Ko, Chang-Hwan Park, et al.
(see pages 16479–16493)
Neuregulins (NRGs) are a family of growth factors that regulate multiple stages of nervous system development, including neuronal migration, synaptogenesis, and myelination. NRGs are transmembrane proteins that, like amyloid precursor protein, are cleaved by β- and γ-secretases to generate a soluble extracellular protein and an intracellular domain (ICD). Most known functions of NRGs in the CNS are mediated by binding of soluble NRG1 to receptor tyrosine kinases of the ErbB family. However, several noncanonical signaling pathways have been described, including regulation of gene transcription by the ICD.
Granule cells in organotypic hippocampal slice cultures 10 d after infection with retrovirus. See Lee et al. for details.
NRG1 is downregulated in the mature brain, but NRG2 expression remains high in neurogenic regions, including the dentate gyrus, throughout adulthood. Therefore, Lee et al. asked whether NRG2 plays a role in incorporating newborn dentate granule cells into neural circuits. To address this question, the authors used retroviruses to express tetracycline-inducible shRNA targeting NRG2 in newborn granule cells. This allowed them to knock down NRG2 during specific periods of granule-cell synaptogenesis.
In organotypic hippocampal slice cultures from rat pups, GABAergic synapses formed on newborn granule cells starting 6 days postinfection (dpi); the amplitude of GABAergic postsynaptic currents (PSCs) increased until 10 dpi. At that time, glutamatergic synapses began to appear, and they continued to grow stronger for several days. Knocking down NRG2 at 4–9 dpi greatly reduced the development of GABAergic responses, without affecting glutamatergic PSCs. Conversely, knocking down NRG2 starting at 7 dpi did not affect GABAergic synapses, but inhibited maturation of glutamatergic synapses. Most interestingly, inhibiting the tyrosine kinase activity of the NRG2 receptor ErbB4 impaired development of GABAergic, but not glutamatergic responses, whereas expressing the NRG2 ICD rescued the effect of NRG2 knockdown on glutamatergic, but not GABAergic synapses.
These results suggest that NRG2 regulates the development of both GABAergic and glutamatergic inputs to newborn granule cells, but it does so through different pathways: GABAergic synaptogenesis requires activation of the ErbB4 tyrosine kinase, while glutamatergic synapse maturation requires signaling via the ICD. Whether NRG2's contribution to synapse formation in newborn granule cells persists into adulthood remains uncertain. If it does, then impaired integration of adult-born granule cells may contribute to conditions linked to impaired NRG–ErbB function, such as schizophrenia.
