Hospitalization for major surgery or critical illness often associates with cognitive decline. Inflammation and dysregulation of the innate immune system can exert broad effects in the periphery and central nervous system (CNS), yet the mechanisms underlying memory impairment after surgery remain poorly understood and without effective therapy. Endogenous regulation of acute inflammation is providing novel approaches to treat several disease states including sepsis, pain, obesity and diabetes. Resolvins are potent endogenous lipid mediators biosynthesized during the resolution phase of acute inflammation that display immunoresolvent actions. Here, using a mouse model of surgery-induced cognitive decline we report that orthopedic surgery affects hippocampal neuronal-glial function, including synaptic transmission and plasticity. Systemic prophylaxis with aspirin-triggered resolvin D1 (AT-RvD1: 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid, as little as 100 ng dose per mouse) improved memory decline following surgery and abolished signs of synaptic dysfunction. Moreover, delayed administration 24 h after surgery also attenuated signs of neuronal dysfunction postoperatively. AT-RvD1 also limited peripheral damage by modulating the release of systemic interleukin (IL)-6 and improved other clinical markers of tissue injury. Collectively, these results demonstrate a novel role of AT-RvD1 in modulating the proinflammatory milieu after aseptic injury and protecting the brain from neuroinflammation, synaptic dysfunction and cognitive decline. These findings provide novel and safer approaches to treat postoperative cognitive decline and potentially other forms of memory dysfunctions.

The role of developmental transcription factors in maintenance of neuronal properties and in disease remains poorly understood. Lmx1a and Lmx1b are key transcription factors required for the early specification of ventral midbrain dopamine (mDA) neurons. Here we show that conditional ablation of Lmx1a and Lmx1b after mDA neuron specification resulted in abnormalities that show striking resemblance to early cellular abnormalities seen in Parkinson's disease. We found that Lmx1b was required for the normal execution of the autophagic-lysosomal pathway and for the integrity of dopaminergic nerve terminals and long-term mDA neuronal survival. Notably, human LMX1B expression was decreased in mDA neurons in brain tissue affected by Parkinson's disease. Thus, these results reveal a sustained and essential requirement of Lmx1b for the function of midbrain mDA neurons and suggest that its dysfunction is associated with Parkinson's disease pathogenesis.

Depression is usually associated with alterations in the monoaminergic system. However, new evidences suggest the involvement of the glutamatergic system in the aetiology of depression. Here we explored the glutamatergic system in a rat model of depression (i.e., the flinders sensitive line (FSL)) to reveal the mechanism underlying the emotional and cognitive aspects associated with the disease. We showed a dramatically elevated level of baseline glutamatergic synaptic transmission by whole-cell recordings as well as impairment in long-term potentiation induced by high-frequency stimulation in hippocampal slices from FSL rats compared with Sprague-Dawley rats. At behavioural level, FSL rats displayed recognition memory impairment in the novel object recognition test. Enantioselective chromatography analysis revealed lower levels of D-serine in the hippocampus of FSL rats and both synaptic plasticity and memory impairments were restored by administration of D-serine. We also observed dysfunctional astrocytic glutamate regulation including downregulation of the glia glutamate transporter GLAST as shown by western blot. One possibility is that the dysfunctional astrocytic glutamate reuptake triggers a succession of events, including the reduction of D-serine production as a safety mechanism to avoid NMDA receptor overactivation, which in turn causes the synaptic plasticity and memory impairments observed. These findings open up new brain targets for the development of more potent and efficient antidepressant drugs.

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The possibility that exposure to general anesthetics during early life results in long-term impairment of neural function attracted considerable interest over the past decade. Extensive laboratory data suggest that administration of these drugs during critical stages of central nervous system development can lead to cell death, impaired neurogenesis, and synaptic growth as well as cognitive deficits. These observations are corroborated by several recent human epidemiological studies arguing that such cognitive impairment might also occur in humans. Despite the potential public health importance of this issue, several important questions remain open. Amongst them, how the duration of anesthesia exposure impact on outcome is as yet not fully elucidated. To gain insight into this question, here we focused on the short- and long-term impact of a 30-min-long exposure to clinically relevant concentrations of sevoflurane in rat pups at 2 functionally distinct stages of the brain growth spurt. We show that this treatment paradigm induced developmental stage-dependent and brain region-specific acute but not lasting changes in dendritic spine densities. Electrophysiological recordings in hippocampal brain slices from adult animals exposed to anesthesia in the early postnatal period revealed larger paired-pulse facilitation but no changes in the long-term potentiation paradigm when compared with nonanesthetized controls. 5-bromo-2-deoxyuridine pulse and pulse-chase experiments demonstrated that neither proliferation nor differentiation and survival of hippocampal progenitors were affected by sevoflurane exposure. In addition, behavioral testing of short- and long-term memory showed no differences between control and sevoflurane-exposed animals. Overall, these results suggest that brief sevoflurane exposure during critical periods of early postnatal development, although it does not seem to exert major long-term effects on brain circuitry development, can induce subtle changes in synaptic plasticity and spine density of which the physiological significance remains to be determined.