BackgroundChronic obstructive pulmonary disease and emphysema are a frequent result of long-term smoking, but the exact mechanisms, specifically which types of cells are associated with the lung destruction, are unclear.Methods and FindingsWe studied different subsets of lymphocytes taken from portions of human lungs removed surgically to find out which lymphocytes were the most frequent, which cell-surface markers these lymphocytes expressed, and whether the lymphocytes secreted any specific factors that could be associated with disease. We found that loss of lung function in patients with chronic obstructive pulmonary disease and emphysema was associated with a high percentage of CD4+ and CD8+ T lymphocytes that expressed chemokine receptors CCR5 and CXCR3 (both markers of T helper 1 cells), but not CCR3 or CCR4 (markers of T helper 2 cells). Lung lymphocytes in patients with chronic obstructive pulmonary disease and emphysema secrete more interferon gamma—often associated with T helper 1 cells—and interferon-inducible protein 10 and monokine induced by interferon, both of which bind to CXCR3 and are involved in attracting T helper 1 cells. In response to interferon-inducible protein 10 and monokine induced by interferon, but not interferon gamma, lung macrophages secreted macrophage metalloelastase (matrix metalloproteinase-12), a potent elastin-degrading enzyme that causes tissue destruction and which has been linked to emphysema.ConclusionsThese data suggest that Th1 lymphoctytes in the lungs of people with smoking-related damage drive progression of emphysema through CXCR3 ligands, interferon-inducible protein 10, and monokine induced by interferon.

Near coincidental pre- and postsynaptic action potentials induce associative long-term potentiation (LTP) or long-term depression (LTD), depending on the order of their timing. Here, we show that in visual cortex the rules of this spike-timing-dependent plasticity are not rigid, but shaped by neuromodulator receptors coupled to adenylyl cyclase (AC) and phospholipase C (PLC) signaling cascades. Activation of the AC and PLC cascades results in phosphorylation of postsynaptic glutamate receptors at sites that serve as specific "tags" for LTP and LTD. As a consequence, the outcome (i.e., whether LTP or LTD) of a given pattern of pre- and postsynaptic firing depends not only on the order of the timing, but also on the relative activation of neuromodulator receptors coupled to AC and PLC. These findings indicate that cholinergic and adrenergic neuromodulation associated with the behavioral state of the animal can control the gating and the polarity of cortical plasticity.

Bipolar disorder, characterized by extreme manic and depressive moods, is a prevalent debilitating disease of unknown etiology. Because mood stabilizers, antipsychotics, antidepressants, and mood-regulating neuromodulators increase the inhibitory serine-phosphorylation of glycogen synthase kinase-3 (GSK3), we hypothesized that deficient GSK3 serine-phosphorylation may increase vulnerability to mood-related behavioral disturbances. This was tested by measuring behavioral characteristics of GSK3α/β21A/21A/9A/9A knockin mice with serine-to-alanine mutations to block inhibitory serine-phosphorylation of GSK3. GSK3 knockin mice displayed increased susceptibility to amphetamine-induced hyperactivity and to stress-induced depressive-like behaviors. Furthermore, serine-phosphorylation of GSK3 was reduced during both mood-related behavioral responses in wild-type mouse brain and in blood cells from patients with bipolar disorder. Therefore, proper control of GSK3 by serine-phosphorylation, which is targeted by agents therapeutic for bipolar disorder, is an important mechanism that regulates mood stabilization, and mice with disabled GSK3 serine-phosphorylation may provide a valuable model to study bipolar disorder.

Lack of a sensory input not only alters the cortical circuitry subserving the deprived sense, but also produces compensatory changes in the functionality of other sensory modalities. Here we report that visual deprivation produces opposite changes in synaptic function in primary visual and somatosensory cortices in rats, which are rapidly reversed by visual experience. This type of bidirectional cross-modal plasticity is associated with changes in synaptic AMPA receptor subunit composition.Loss of vision is usually accompanied by the increased functionality of other sensory modalities 1,2 . Systems-level analyses of cross-modal plasticity have revealed anatomical and functional rewiring of cortical circuits 3 . However, little is known about the cellular and molecular mechanisms underlying this type of plasticity. Here we examined whether manipulation of visual experience can induce bidirectional cross-modal plasticity of synaptic function in primary sensory cortices, and investigated the molecular mechanisms underlying this form of plasticity.To study cross-modal changes in synaptic function by visual deprivation, we dark-reared 4-week-old Long-Evans rats for a period of 1 week and then measured AMPA receptor (AMPAR)-mediated miniature excitatory postsynaptic currents (mEPSCs) in layer 2/3 pyramidal neurons in slices from primary visual, somatosensory and auditory cortex (Supplementary Methods online). In visual cortex, dark rearing produced an increase in mESPC amplitude that was reversed by re-exposing the rats to lighted conditions for 2 d Correspondence should be addressed to H.-K.L. (hlee21@umd.edu). 4 Current address: Brain Science Institute, Riken, Wako City, Saitama, Japan. 5 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Neuroscience website. AUTHOR CONTRIBUTIONSA.G. and B.J. conducted the electrophysiology experiments (mEPSC recordings and rectification measurements, respectively) and assisted in writing the manuscript; L.W.X. and L.S. performed the biochemistry experiments; A.K. oversaw the electrophysiology (rectification measurements), contributed to discussions on experimental designs and collaborated on manuscript writing; H.-K.L. designed the studies, oversaw experiments, contributed to the electrophysiology (mEPSC recordings) and biochemistry and wrote the manuscript. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. (normal-reared (NR): 10.7 ± 0.6 pA, n = 8; dark-reared (DR): 12.4 ± 0.4 pA, n = 16; re-exposure to light (L): 10.7 ± 0.4 pA, n = 13; analysis of variance (ANOVA): F 2,34 = 5.968, P < 0.01; Fig. 1a). Notably, we observed the opposite changes in somatosensory cortex, where 1 week of dark rearing decreased the amplitude of mEPSCs and 2 d of light exposure reversed this effect (NR: 13.8 ± 0.8 pA, n = 12; DR: 11.3 ± 0.7 pA, n = 16; L: 14.1 ± 0.9 pA, n = 16; ANOVA: F 2,40 = 3.830, P < 0.04; Fig. 1b). Changes in synaptic transmission by dark rearing seems to be general for pr...

Stress of the endoplasmic reticulum (ER), which is associated with many neurodegenerative conditions, can lead to the elimination of affected cells by apoptosis through only partially understood mechanisms. Thapsigargin, which causes ER stress by inhibiting the ER Ca 2؉ -ATPase, was found to not only activate the apoptosis effector caspase-3 but also to cause a large and prolonged increase in the activity of glycogen synthase kinase-3␤ (GSK3␤). Activation of GSK3␤ was obligatory for thapsigargin-induced activation of caspase-3, because inhibition of GSK3␤ by expression of dominantnegative GSK3␤ or by the GSK3␤ inhibitor lithium blocked caspase-3 activation. Thapsigargin treatment activated GSK3␤ by inducing dephosphorylation of phospho-Ser-9 of GSK3␤, a phosphorylation that normally maintains GSK3␤ inactivated. Caspase-3 activation induced by thapsigargin was blocked by increasing the phosphorylation of Ser-9-GSK3␤ with insulin-like growth factor-1 or with the phosphatase inhibitors okadaic acid and calyculin A, but the calcineurin inhibitors FK506 and cyclosporin A were ineffective. Insulin-like growth factor-1, okadaic acid, calyculin A, and lithium also protected cells from two other inducers of ER stress, tunicamycin and brefeldin A. Thus, ER stress activates GSK3␤ through dephosphorylation of phospho-Ser-9, a prerequisite for caspase-3 activation, and this process is amenable to pharmacological intervention.