This Week in The Journal

Cellular/Molecular

Anti-Hebbian LTD Cancels Self-Generated Sensory Signals in Fish

Erik Harvey-Girard, John Lewis, and Leonard Maler

To effectively detect environmental features, an animal must differentiate stimuli that result from its own actions from those produced externally. Electric fish emit electric pulses, creating an electric field that is detected by electroreceptors along the fish's body. Environmental objects create spatially localized amplitude modulations in the electric field, and these distortions are used to detect objects. Tail movements, which vary the distance between the electric organ and electroreceptors, produce spatially diffuse distortions that affect receptors along the entire length of the fish. A negative image of these global signals is transmitted via cerebellar parallel fibers to the central target of electrosensory afferents (principal cells of the electrosensory lateral line lobe) to cancel neural activity produced by self-generated field distortions. Harvey-Girard et al. suggest that this cancellation results in part from long-term depression (LTD) of parallel fiber input to principal cells, and that this occurs when both presynaptic and postsynaptic cells fire bursts of spikes within a short temporal window.

Development/Plasticity/Repair

Blood Fibrinogen Triggers Astrogliosis after Brain Injury

Christian Schachtrup, Jae K. Ryu, Matthew J. Helmrick, Eirini Vagena, Dennis K. Galanakis, et al.

(see pages 5843–5854)

CNS damage triggers reactive astrogliosis. In severe cases, astrocytes proliferate and form a long-lasting glial scar comprised mainly of chondroitin sulfate proteoglycans (CSPGs). Glial scars prevent regrowth of axons and thus are a major impediment to functional recovery. Although the initial molecular triggers of astrogliosis remain elusive, tumor growth factor β (TGF-β) is thought to trigger CSPG secretion from astrocytes soon after injury. Schachtrup et al. have now identified the blood protein fibrinogen as an inducer of reactive astrogliosis and CSPG deposition. After cortical injury in mice, deposits of fibrin—a clotting protein formed from fibrinogen—colocalized with reactive astrogliosis. Injection of exogenous fibrinogen induced astrogliosis and CSPG deposition. The authors discovered that a latent form of TGF-β was bound to fibrinogen in plasma and was activated upon exposure to cultured astrocytes. In fibrinogen-null mice, injury-induced reactive gliosis, TGF-β levels, and CSPG deposits were greatly reduced, and in wild-type mice, TGF-β receptor inhibitor prevented fibrinogen-induced astrogliosis.

Levels of fibrin (red) and astrogliosis, indicated by glial fibrillary acidic protein labeling (green), are normally low in mouse brain (left), but both increase after cortical injury (right). See the article by Schachtrup et al. for details.

Behavioral/Systems/Cognitive

Brain Leptin Regulates Systemic Immune Function

Johannes Tschöp, Ruben Nogueiras, Sarah Haas-Lockie, Kevin R. Kasten, Tamara R. Castañeda, et al.

(see pages 6036–6047)

Leptin, a cytokine produced by adipocytes, plays a major role in food intake, weight control, and reproductive function. Leptin also activates and stimulates proliferation of immune cells, and leptin-resistant people are prone to infections. Having noticed a high susceptibility to sepsis—a systemic inflammatory response to infection that can lead to organ failure—in patients with leptin deficiency, and that low leptin levels are correlated with high mortality in sepsis patients, Tschöp et al. hypothesized that leptin has an important role in systemic immune defenses. Leptin-deficient mice had a higher incidence of kidney and liver damage and died sooner after experimentally induced sepsis than wild-type mice. Bacteria counts and interleukin 6 levels were higher in blood from mutant mice, and phagocytosis by neutrophils was reduced. Interestingly, injection of leptin directly into the brains of leptin-deficient mice increased survival, normalized interleukin 6 levels, and reduced kidney damage, suggesting that leptin actions in the brain regulate systemic immune function.

Neurobiology of Disease

Autoantibodies against NMDA Receptors Trigger Internalization

Ethan G. Hughes, Xiaoyu Peng, Amy J. Gleichman, Meizan Lai, Lei Zhou, et al.

(see pages 5866–5875)

In the past few years, autoantibodies against the NMDA receptor NR1 subunit have been identified in many patients with encephalitis. The autoantibodies are thought to be generated when tumors outside the brain, often in the ovaries, express NMDA receptors. The autoantibodies trigger psychiatric disturbances, memory loss, and seizures, which can often be reversed by immunotherapy and tumor removal. Hughes et al. show that antibody-containing CSF from patients caused internalization of NMDA receptors in cultured rat hippocampal neurons without affecting other synaptic proteins, including AMPA receptors, GABA receptors, a glutamate transporter, and the postsynaptic density protein PSD-95. Moreover, the antibodies did not obviously affect synaptic density, dendritic morphology, or cell survival. Surface expression of NMDA receptors returned to normal levels within 4 days after antibodies were removed. In postmortem patients, NMDA receptor density was decreased in the hippocampus, and likewise, infusion of patients' CSF into rat brain caused receptor internalization in the hippocampus.