The Chemokine RANTES Exerts Dual Effects on Neurons
Veronica Musante, Fabio Longordo, Elisa Neri, Marco Pedrazzi, Fotios Kalfas, Paolo Severi, Maurizio Raiteri, and Anna Pittaluga
(see pages 12231–12240)
Chemokines are small secreted proteins that attract leukocytes to sites of inflammation. In addition to their roles in the immune system, some chemokines bind to receptors on neurons and modulate neurotransmitter release. The chemokine RANTES is one of three chemokines that bind to CCR5—a G-protein-coupled receptor required by HIV to infect T cells. Normally, RANTES is nearly undetectable in CSF, but levels substantially increase under HIV infection and other inflammatory conditions. Interestingly, RANTES inhibits HIV infection at low concentrations, but might enhance infection at high concentrations. Musante et al. report that RANTES also has dual effects on glutamate release. In synaptosomes and human neocortical slices, RANTES increased glutamate release by activating a pathway involving a tyrosine kinase, phospholipase C, and inositol trisphosphate (IP3) receptor-mediated calcium release from intracellular stores. When neurons were depolarized, RANTES inhibited release via a different signaling pathway, which may involve adenylate cyclase and protein kinase A.
Stem-Cell-Derived Motor Neurons Reinnervate Muscle
Damien C. Yohn, Gareth B. Miles, Victor F. Rafuse, and Robert M. Brownstone
(see pages 12409–12418)
This week, Yohn et al. moved a step closer to developing stem-cell-based treatments for neurodegenerative diseases such as amyotrophic lateral sclerosis. Mouse embryonic stem cells were first driven to differentiate into motor neurons by culturing them with specific molecules involved in cell fate determination. Next, the sciatic nerve was severed in adult mice, and the differentiated stem cells were transplanted into a distal branch of the nerve. The transplanted cells soon extended neurites along the nerve, and many of these fibers became myelinated and reinnervated the medial gastrocnemius muscle. Stimulation of the reinnervating fibers produced muscle twitches that had ∼40% of the normal twitch force. The stem-cell-derived motor neurons reduced muscle atrophy after sciatic nerve lesion, but the proportion of slow, fatigue-resistant muscle fibers was increased compared to normal. This change likely resulted from the firing pattern of the reinnervating fibers, because these patterns are known to specify muscle properties.
Rats Do Not Detect the Activity of Single Thalamic Neurons
Birgit C. Voigt, Michael Brecht, and Arthur R. Houweling
(see pages 12362–12367)
Humans can detect a stimulus that activates a single sensory afferent. Given that each afferent's activity influences the firing of millions of CNS cells, how many central neurons must be active for a stimulus to be detected? To answer this question, Voigt et al. trained rats to report (with licks) microstimulation in the thalamic whisker field. They then stimulated single thalamic neurons juxtacellularly. Although stimulation produced an eightfold increase in spiking over spontaneous rates, it did not elicit lick responses above chance levels. This was surprising, because stimulation of single neurons in the barrel cortex was previously shown to elicit a behavioral response, and 10 times more neurons represent a single whisker in the cortex than in the thalamus. Possible explanations for this difference include a higher spontaneous firing rate in thalamus, which would decrease the signal-to-noise ratio, and extensive recurrent connections in cortex, which might amplify the signal from a single neuron.
Neurobiology of Disease
A Single Cysteine Makes HIV Tat Protein Neurotoxic
Wenxue Li, Yan Huang, Rollie Reid, Joseph Steiner, Tanya Malpica-Llanos, Thomas A. Darden, Susarla K. Shankar, Anita Mahadevan, Parthasarthy Satishchandra, and Avindra Nath
(see pages 12190–12198)
Different clades of HIV infect people in different regions of the world, resulting in different regional pathologies. For example, clade B produces progressive neurodegeneration, whereas clade C causes milder cognitive impairment. HIV-associated neuropathology is thought to be caused by Tat proteins, which are secreted by infected macrophages and activate NMDA receptors. Li et al. found that clade C Tat was less toxic to cultured neurons than clade B Tat, and this difference resulted from the mutation of a single cysteine residue to serine in clade C. Mutating the serine back to cysteine made clade C Tat toxic, whereas mutating cysteine to serine eliminated the toxicity of clade B Tat. Molecular modeling suggested that the cysteine in Tat interacts with a cysteine in the NMDA receptor, disrupting a disulfide bond that normally forms within the receptor. This leads to persistent activity of the NMDA receptor, and results in excitotoxicity.