Cellular/Molecular
Neuropsin Frees Neuregulin to Activate Its Receptor
Hideki Tamura, Miho Kawata, Seiya Hamaguchi, Yasuyuki Ishikawa, and Sadao Shiosaka
(see pages 12657–12672)
Neuropsin, an extracellular protease, is highly expressed in the limbic system. Stimuli that induce various forms of synaptic plasticity cause brief, NMDA-receptor-dependent activation of neuropsin and increase neuropsin transcription; neuropsin knock-out reduces early long-term potentiation (E-LTP) elicited by weak stimulation of Schaffer collaterals in mouse hippocampal slices. Although some neuropsin substrates have been identified through candidate-target approaches, a systematic screen has not been possible, largely because the interaction between neuropsin and its substrates is too brief to permit coimmunoprecipitation. Tamura et al. circumvented this problem by transfecting cultured hippocampal neurons with recombinant neuropsin harboring a point mutation that allowed target binding, but not cleavage. Neuregulin-1 was identified as a major neuropsin target, and the two proteins appeared to interact near postsynaptic densities. Further experiments demonstrated that neuropsin-mediated removal of neuregulin's heparin-binding domain was required for activation of the neuregulin-1 receptor ErbB4, which in turn was required for induction of E-LTP.
Development/Plasticity/Repair
Mec-17 Acetyltransferase Is Required for Neuronal Migration
Lei Li, Dan Wei, Qiong Wang, Jing Pan, Rong Liu, et al.
(see pages 12673–12683)
Cortical pyramidal neurons are generated in the ventricular zone and migrate outward through the intermediate zone, subplate, and the expanding cortical plate to reach their final position. Within the intermediate zone, newborn neurons extend and retract several neurites, exhibiting a multipolar morphology before eventually acquiring a bipolar morphology with a leading process oriented toward the cortical plate. They then begin radial migration. Migration requires stable microtubules, which are marked by acetylation of α-tubulin subunits; but whether α-tubulin acetylation is necessary for microtubule stabilization and neuronal migration is unclear. Li et al. report that knocking down Mec-17, the primary mediator of α-tubulin acetylation, greatly impaired neuronal migration in embryonic mice. Many Mec-17-deficient neurons remained in the intermediate zone, exhibiting a multipolar morphology, and many never migrated appropriately. Although the results suggest that Mec-17 affects microtubule stability and neuronal migration via α-tubulin acetylation, results from rescue experiments suggest that Mec-17 has acetylation-independent effects as well.
Behavioral/Systems/Cognitive
β1 Integrins Define a Newly Identified Consolidation Phase
Alex H. Babayan, Enikö A. Kramár, Ruth M. Barrett, Matiar Jafari, Jakob Hättig, et al.
(see pages 12854–12861)
β1 integrins form transmembrane receptors that, upon binding to extracellular ligands, precipitate the formation of large protein complexes that link the extracellular matrix to the cytoskeleton. Assembly and disassembly of these linkages is required for migration and neurite growth. β1 integrins also contribute to long-term potentiation (LTP): blocking them prevents stimulation-induced actin polymerization and causes LTP to decay to baseline. Babayan et al. found that LTP-inducing theta-burst stimulation (TBS) in rat hippocampal slices caused surprisingly short-lived (<7 min) activation of β1 integrin and one of its downstream effectors. The receptors then entered a refractory state lasting ∼45 min, during which they were not activated by additional TBS. Remarkably, blocking β1 activation during this period caused LTP to decay to baseline, suggesting the β1 refractory period marks a previously unidentified phase of LTP consolidation. Blocking β1-integrin activation in vivo shortly after mice performed a task impaired long-term memory, demonstrating the importance of this phase.
TBS (red arrow) induced LTP in hippocampal slices. Blocking β1 integrins (filled circles) 30–60 min after TBS (bar) diminished LTP, whereas control IgG (open circles) did not. See the article by Babayan et al. for details.
Neurobiology of Disease
Neuronally Produced Superoxide Affects Nearby Cells
Reno Reyes, Angela Brennan, Yiguo Shen, Ylva Baldwin, and Raymond Swanson
(see pages 12973–12978)
Activation of NMDA receptors (NMDARs) leads to production of superoxide, which regulates signaling cascades involved in synaptic plasticity. Under normal conditions, superoxide dismutase quickly scavenges superoxide, but with prolonged NMDAR activation, excessive superoxide can contribute to oxidative stress and cell death. NMDAR-dependent superoxide production is mediated by NADPH oxidase 2 (NOX2), which assembles upon phosphorylation of its p47phox subunit. NOX2 can assemble on intracellular or plasma membranes, leading to superoxide production inside or outside cells, respectively; but only extracellularly produced superoxide can affect nearby cells. The location of NOX2 assembly in neurons is currently unknown, but new evidence suggests it occurs on plasma membranes. Reyes et al. cultured cortical neurons from p47phox-null mice, then reintroduced p47phox into ∼10% of cells. Subsequent NMDA treatment induced oxidative damage in nearby neurons. Notably, p47phox-expressing neurons exhibited oxidative damage only if they were near another p47phox-expressing neuron, suggesting that super oxide acted exclusively outside the cell that produced it.
