Cellular/Molecular
P/Q Channel Slots Accept N-Type Channels
Yu-Qing Cao and Richard W. Tsien
(see pages 4536–4546)
Neurotransmitter release is triggered by the opening of N- and P/Q-type calcium channels clustered near vesicle release sites. In cultured hippocampal neurons from mice, subtype-specific blockers of N and P/Q channels each reduce EPSC size in postsynaptic neurons by ∼45%, suggesting that the channel subtypes contribute equally to neurotransmitter release. Cao and Tsien previously showed that overexpressing P/Q channels did not increase EPSC size nor alter the contribution of P/Q channels, suggesting that a limited number of channel-specific binding sites (“slots”) are present at release sites and that these are normally filled to capacity. The authors now report that although overexpressing N channels did not increase EPSC amplitude, it nearly doubled the effect of N-channel blockers on EPSC size and reduced the contribution of P/Q channels. Altogether, the results suggest that although some slots are N-channel specific, others can accept either P/Q or N channels. Thus, changes in expression of channel subtypes would differentially affect synaptic transmission.
Development/Plasticity/Repair
Peripheral Nerve Injury Reduces Gene Expression via NRSF
Hitoshi Uchida, Lin Ma, and Hiroshi Ueda
(see pages 4806–4814)
Peripheral nerve injury causes multiple symptoms, including tingling and reduced sensation. Some symptoms are attributed to C-fibers, which exhibit increased pain thresholds and reduced responsiveness to μ-opioids. These, in turn, result from down-regulation of Nav1.8 sodium channels and μ-opioid receptors (MOR), respectively. Uchida et al. report that in mice, the genes encoding Nav1.8 and MOR have neuron-restrictive silencer element (NRSE) sequences. These sequences bind neuron-restrictive silencer factor (NRSF), which recruits histone deacetylase to the site and thereby represses transcription. Peripheral nerve injury caused increased expression of NRSF in dorsal root ganglion neurons, increased binding of NRSF to the NRSEs in the Nav1.8 and MOR genes, and decreased histone acetylation at these sites. Knockdown of NRSF prevented injury-induced down-regulation of Nav1.8 and MORs, as well as two transient receptor potential channels. Moreover, NRSF knockdown blocked injury-induced hypoesthesia and loss of morphine analgesia without affecting neuropathic pain symptoms mediated by A-fibers.
Behavioral/Systems/Cognitive
Correlated Activity Adds Little Information
Masafumi Oizumi, Toshiyuki Ishii, Kazuya Ishibashi, Toshihiko Hosoya, and Masato Okada
(see pages 4815–4826)
Sensory neurons do not encode stimuli perfectly: even responses to identical stimuli vary from trial to trial. Nonetheless, one can determine the probability that a given stimulus occurred given the response of a neuron. But just as neurons imperfectly encode stimuli, downstream neurons are likely to decode the information imperfectly. Therefore, Oizumi et al. introduced a method for quantifying the amount of information that would be lost by using a suboptimal decoder, and they used this method to explore how important synchronous firing across neurons is. They found that although spiking in response to a natural-scene movie was highly correlated across retinal neurons, ignoring correlations only slightly decreased the amount of information available in the responses. They conclude that the brain can differentiate stimuli almost as well with a simple decoding strategy that does not monitor simultaneous activity as with more complex decoding strategies that take correlations into account.
Neurobiology of Disease
One Misfolded Protein Begets Another
Rodrigo Morales, Lisbell D. Estrada, Rodrigo Diaz-Espinoza,Diego Morales-Scheihing, Maria C. Jara, et al.
(see pages 4528–4535)
Several neurodegenerative diseases, including Alzheimer's (AD) and transmissible spongiform encephalopathy (TSE), involve misfolding of proteins into conformations that promote oligomerization, fibril formation, and ultimately deposition of large amyloid aggregates. Although each disease is attributed to misfolding of a specific protein, other misfolded proteins are often present as well. For example, abnormally folded prion protein (PrPSc), the causal agent in TSE, is often present in β-amyloid (Aβ) plaques in AD, and Aβ deposition is often found in TSE. Morales et al. therefore asked whether accumulation of one protein promotes accumulation of another. Inoculating mice that express an AD-associated form of Aβ with brain homogenate containing PrPSc accelerated accumulation of both proteins. The proteins were colocalized in both AD-like plaques and TSE-like diffuse deposits. Furthermore, PrPSc promoted Aβ aggregation in vitro and Aβ oligomers produced conformational changes in recombinant PrP, suggesting that aggregation of one misfolded protein can directly promote aggregation of another.
Astrogliosis in mice expressing a mutant form of Aβ (left) is worsened by injecting PrPSc. See the article by Morales et al. for details.
