Mind Bomb 1 and Neuronal Morphogenesis
Eun-Ah Choe, Lujian Liao, Jian-Ying Zhou, Dongmei Cheng, Duc M. Duong, Peng Jin, Li-Huei Tsai, and Junmin Peng
(see pages 9503–9512)
In this week's Journal, Choe et al. used proteomics to identify molecular regulators of neuronal morphogenesis. They detected a ubiquitin ligase mind bomb 1 (Mib1) in the postsynaptic density. Overexpression of Mib1 inhibited neurite outgrowth in cultured neurons. Using glutathione S-transferase (GST) affinity purification, the authors isolated proteins of the so-called interactome of Mib1, including cyclin-dependent kinase 5 (CDK5). This normally inactive deubiquitinating enzyme is activated by an atypical cyclin-like subunit, p35. The p35 subunit interacted directly with the N-terminal domain of Mib1, linking Mib1 with CDK5. Mib1 ubiquitination led to internalization and relocalization of p35 in cell cultures, whereas increased expression of p35 reduced Mib1. This downregulation arose from CDK5/p35 kinase activity. The molecules had opposite effects on neurite growth as well, with p35 expression rescuing Mib1 inhibition. In Drosophila, the authors also saw opposing effects of Mib1 and CDK5/p35 on eye development.
Conductive Hearing Loss and Synaptic Function in the Auditory Cortex
Han Xu, Vibhakar C. Kotak, and Dan H. Sanes
(see pages 9417–9426)
Sensorineural hearing loss (SNHL), caused by cochlear damage or ablation, has profound effects on central processing. This week, Xu et al. set out to determine how the more modest sensory deprivation associated with conductive hearing loss (CHL) impacted central auditory function. The authors stimulated the gerbil ventral medial geniculate nucleus (MGv) with stimulus trains similar to tone-evoked firing and then recorded from auditory cortex layer 2/3 pyramidal neurons. Compared with controls, postsynaptic potentials were smaller in gerbils with either SNHL or CHL. The synaptic depression normally seen with stimulation of MGv was more rapid in hearing-impaired animals. Hearing loss also increased firing probability, spike latency, and spike jitter, resulting in reduced signal fidelity. Like SNHL neurons, CHL neurons had somewhat depolarized resting membrane potentials. All together, the data suggest that changes in central pathways may contribute to auditory dysfunction in mild hearing loss.
Selective Auditory Attention in Humans
Aurélie Bidet-Caulet, Catherine Fischer, Julien Besle, Pierre-Emmanuel Aguera, Marie-Helene Giard, and Olivier Bertrand
(see pages 9252–9261)
Despite the E. F. Hutton commercial of some years ago, it's not so easy to pick out one conversation in a noisy, crowded place. The brain accomplishes this task not only by focusing attention on the salient sound but also by tuning out other sounds. To investigate this issue, Bidet-Caulet et al. studied subjects who were being monitored with intracranial electrodes for possible epilepsy surgery. This situation gave the authors the opportunity to make electrophysiological recordings in the primary auditory cortex of the temporal lobe. Subjects were presented with two amplitude-modulated auditory streams and instructed to focus on one of them. Selective attention affected the evoked responses in primary and associative auditory areas. Greater neural representation was afforded to the most relevant information, and in the left hemisphere, selective attention was enhanced by actively reducing the neural representation of irrelevant information.
Neurobiology of Disease
ATP Signaling and Oligodendrocyte Toxicity
Carlos Matute, Iratxe Torre, Fernando Pérez-Cerdá, Alberto Pérez-Samartín, Elena Alberdi, Estibaliz Etxebarria, Amaia M. Arranz, Rivka Ravid, Alfredo Rodríguez-Antigüedad, MaríaVictoria Sánchez-Gómez, and María Domercq
(see pages 9525–9533)
Excitotoxicity used to be synonymous with too much glutamate, but when it comes to oligodendrocytes, it seems that excitotoxicity also can mean too much ATP. This week, Matute et al. provide evidence that ATP can cause excitotoxic damage by activating P2X7 purinergic receptors and increasing intracellular calcium. In cultured rat oligodendrocytes, ATP triggered nondesensitizing P2X7 currents that proved toxic under conditions of sustained ATP exposure. Toxicity was prevented when calcium was removed from the media, or in the presence of P2X receptor antagonists. In whole optic nerves, both isolated and in vivo, ATP perfusion increased oligodendrocyte death. P2X agonists produced oligodendrocyte death, demyelination, and axonal damage reminiscent of multiple sclerosis lesions. P2X7 antagonists reduced motor deficits and demyelination in mice, in which experimental autoimmune encephalomyelitis (EAE) had been induced by myelin oligodendrocyte glycoprotein (MOG) immunization. ATP-induced oligodendrocyte death could contribute to the tissue damage associated with EAE and multiple sclerosis.