This Week in The Journal

Cellular/Molecular

Calcium Channels Help Organize Active Zones

Jie Chen, Sara E. Billings, and Hiroshi Nishimune

For synapses to function, neurotransmitter release sites must form directly opposite postsynaptic receptor clusters. This is ensured by molecular communication between axon terminals and their targets. One pair of communicating molecules is laminin β2, secreted by muscles at the neuromuscular junction (NMJ), and voltage-sensitive calcium channels (VSCCs), which are expressed in axon terminals. Knocking out P/Q calcium channels reduces the number of active zones per NMJ. Chen et al. found that knocking out N calcium channels also reduced the number of active zones, and knocking out both channels caused more severe reductions, greatly decreasing the ability of motor nerves to elicit muscle action potentials. They report that Bassoon, an active zone-specific scaffolding protein that helps load vesicles at release sites, binds directly to VSCCs. In mice lacking both N and P/Q channels, fewer active zones formed, the area of Bassoon expression decreased, and fewer vesicles docked at each release site, suggesting that VSCCs help organize the active zone cytomatrix.

The synaptic vesicle-associated protein synapsin I (green) clustered normally at NMJs (red) and was present at low levels in axons (blue) in muscle of mice lacking P/Q- and N-type calcium channels. See the article by Chen et al. for details.

Development/Plasticity/Repair

Drosophila Neuroligin Is Required for Synaptic Maturation

Mingkuan Sun, Guanglin Xing, Liudi Yuan, Guangming Gan, David Knight, et al.

(see pages 687–699)

Two other molecules involved in trans-synaptic communication are neurexins and neuroligins, adhesion molecules that are expressed presynaptically and postsynaptically, respectively. Although not required for initial synapse formation, these molecules are essential for synaptic maturation. Sun et al. investigated the role of these molecules at Drosophila synapses. Drosophila neuroligin 2 (dnl2) was found at developing and mature synapses throughout the nervous system, including at neuromuscular junctions (NMJs). Knocking out dnl2 in muscle reduced larval locomotion while slightly increasing the amplitude and decreasing the rise and decay times of evoked synaptic responses. Knock-out also decreased paired-pulse facilitation, suggesting that it increased presynaptic release probability. Although the overall pattern of muscle innervation was maintained, the number of synaptic boutons was reduced. In contrast, the number of active zones per bouton and the number of postsynaptic densities increased. Knocking out Drosophila neurexin along with dnl2 produced greater locomotor and morphological defects, suggesting that these molecules act in parallel to maintain synaptic function.

Behavioral/Systems/Cognitive

Serotonin Neurons Fire While Rats Wait

Katsuhiko Miyazaki, Kayoko W. Miyazaki, and Kenji Doya

(see pages 469–479)

Serotonin is involved in many normal and abnormal brain processes, including sleep, depression, motor function, aggression, impulsivity, attention deficit disorder, and obsessive–compulsive disorder. Serotonin also regulates mesolimbic dopaminergic neurons and other neurons involved in reward processing. Serotonergic neurons have been proposed to play a role in reward valuation, but their exact role in reward is unclear. Therefore, Miyazaki et al. recorded single-unit activity of putative serotonergic neurons in the dorsal raphe nucleus while rats performed a task that required moving between three locations and waiting at each for an auditory cue or reward. Neuronal firing increased during the waiting period, and animals waited for a reward or cue only as long as firing remained elevated: when rats moved to another site prematurely, neuronal firing subsided before the move. These results suggest that serotonergic neuron activity is involved in waiting for rewards or controlling the impulse to move on.

Neurobiology of Disease

Blocking EMMPRIN Reduces MS-Like Symptoms in Mouse Model

Smriti M. Agrawal, Claudia Silva, Wallace W. Tourtellotte, and V. Wee Yong

(see pages 669–677)

Multiple sclerosis (MS) is caused by chronic inflammation—often resulting from an autoimmune response—that results in demyelination and axonal degeneration in the CNS. Injection of myelin protein fragments in mice produces a similar disease, experimental autoimmune encephalomyelitis (EAE). In EAE, T cells that recognize injected peptides proliferate in the periphery and then cross the blood–brain barrier to infiltrate the brain. The latter depends in part on upregulation of matrix metalloproteinases (MMPs), which cleave components of the extracellular matrix and contribute to demyelination and axonal degeneration. MMPs are regulated by extracellular matrix metalloproteinase inducer (EMMPRIN). Agrawal et al. report that EMMPRIN levels are increased in brain from MS patients, and it colocalizes with infiltrating leukocytes and resident CNS cells. EMMPRIN levels also increased in mice with EAE. An antibody that blocked EMMPRIN function lessened EAE-induced paralysis, lowered activity of MMPs in the brain, and reduced the number of infiltrating T cells, suggesting that it might treat MS.