Nature medicine
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The term spreading depolarization describes a wave in the gray matter of the central nervous system characterized by swelling of neurons, distortion of dendritic spines, a large change of the slow electrical potential and silencing of brain electrical activity (spreading depression). In the clinic, unequivocal electrophysiological evidence now exists that spreading depolarizations occur abundantly in individuals with aneurismal subarachnoid hemorrhage, delayed ischemic stroke after subarachnoid hemorrhage, malignant hemispheric stroke, spontaneous intracerebral hemorrhage or traumatic brain injury. ⋯ Resistance vessels respond to it with tone alterations, causing either transient hyperperfusion (physiological hemodynamic response) in healthy tissue or severe hypoperfusion (inverse hemodynamic response, or spreading ischemia) in tissue at risk for progressive damage, which contributes to lesion progression. Therapies that target spreading depolarization or the inverse hemodynamic response may potentially treat these neurological conditions.
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Hypofunction of the N-methyl D-aspartate subtype of glutamate receptor (NMDAR) is hypothesized to be a mechanism underlying cognitive dysfunction in individuals with schizophrenia. For the schizophrenia-linked genes NRG1 and ERBB4, NMDAR hypofunction is thus considered a key detrimental consequence of the excessive NRG1-ErbB4 signaling found in people with schizophrenia. However, we show here that neuregulin 1β-ErbB4 (NRG1β-ErbB4) signaling does not cause general hypofunction of NMDARs. ⋯ NRG1β-ErbB4 signaling prevented induction of long-term potentiation at hippocampal Schaffer collateral-CA1 synapses and suppressed Src-dependent enhancement of NMDAR responses during theta-burst stimulation. Moreover, NRG1β-ErbB4 signaling prevented theta burst-induced phosphorylation of GluN2B by inhibiting Src kinase activity. We propose that NRG1-ErbB4 signaling participates in cognitive dysfunction in schizophrenia by aberrantly suppressing Src-mediated enhancement of synaptic NMDAR function.