Matrix metalloproteinase‐9 (MMP‐9) is a member of the metzincin family of mostly extracellularly operating proteases. Despite the fact that all of these enzymes might be target promiscuous, with largely overlapping catalogs of potential substrates,MMP‐9 has recently emerged as a major and apparently unique player in brain physiology and pathology. The specificity ofMMP‐9 may arise from its very local and time‐restricted actions, even when released in the brain from cells of various types, including neurons, glia, and leukocytes. In fact, the quantity ofMMP‐9 is very low in the naive brain, but it is markedly activated at the levels of enzymatic activity, protein abundance, and gene expression following various physiological stimuli and pathological insults. NeuronalMMP‐9 participates in synaptic plasticity by controlling the shape of dendritic spines and function of excitatory synapses, thus playing a pivotal role in learning, memory, and cortical plasticity. When improperly unleashed,MMP‐9 contributes to a large variety of brain disorders, including epilepsy, schizophrenia, autism spectrum disorder, brain injury, stroke, neurodegeneration, pain, brain tumors, etc. The foremost mechanism of action ofMMP‐9 in brain disorders appears to be its involvement in immune/inflammation responses that are related to the enzyme's ability to process and activate various cytokines and chemokines, as well as its contribution to blood–brain barrier disruption, facilitating the extravasation of leukocytes into brain parenchyma. However, another emerging possibility (i.e., the control ofMMP‐9 over synaptic plasticity) should not be neglected. The translational potential ofMMP‐9 has already been recognized in both the diagnosis and treatment domains. The most striking translational aspect may be the discovery ofMMP‐9 up‐regulation in a mouse model of Fragile X syndrome, quickly followed by human studies and promising clinical trials that have sought to inhibitMMP‐9. With regard to diagnosis, suggestions have been made to useMMP‐9 alone or combined with tissue inhibitor of matrix metalloproteinase‐1 or brain‐derived neurotrophic factor as disease biomarkers. image MMP‐9, through cleavage of specific target proteins, plays a major role in synaptic plasticity and neuroinflammation, and by those virtues contributes to brain physiology and a host of neurological and psychiatric disorders.This article is part of the60th Anniversary special issue.

The past 20 years have resulted in unprecedented progress in understanding brain energy metabolism and its role in health and disease. In this review, which was initiated at the 14th International Society for Neurochemistry Advanced School, we address the basic concepts of brain energy metabolism and approach the question of why the brain has high energy expenditure. Our review illustrates that the vertebrate brain has a high need for energy because of the high number of neurons and the need to maintain a delicate interplay between energy metabolism, neurotransmission, and plasticity. Disturbances to the energetic balance, to mitochondria quality control or to glia–neuron metabolic interaction may lead to brain circuit malfunction or even severe disorders of the CNS. We cover neuronal energy consumption in neural transmission and basic (‘housekeeping’) cellular processes. Additionally, we describe the most common (glucose) and alternative sources of energy namely glutamate, lactate, ketone bodies, and medium chain fatty acids. We discuss the multifaceted role of non‐neuronal cells in the transport of energy substrates from circulation (pericytes and astrocytes) and in the supply (astrocytes and microglia) and usage of different energy fuels. Finally, we address pathological consequences of disrupted energy homeostasis in the CNS. image

Background: Common ragweed has been spreading as a neophyte in Europe. Elevated CO₂ levels, a hallmark of global climate change, have been shown to increase ragweed pollen production, but their effects on pollen allergenicity remain to be elucidated.Methods: Ragweed was grown in climate‐controlled chambers under normal (380 ppm, control) or elevated (700 ppm, based on RCP4.5 scenario) CO₂ levels. Aqueous pollen extracts (RWE) from control‐ or CO₂‐pollen were administered in vivo in a mouse model for allergic disease (daily for 3‐11 days, n = 5) and employed in human in vitro systems of nasal epithelial cells (HNECs), monocyte‐derived dendritic cells (DCs), and HNEC‐DC co‐cultures. Additionally, adjuvant factors and metabolites in control‐ and CO₂‐RWE were investigated using ELISA and untargeted metabolomics.Results: In vivo, CO₂‐RWE induced stronger allergic lung inflammation compared to control‐RWE, as indicated by lung inflammatory cell infiltrate and mediators, mucus hypersecretion, and serum total IgE. In vitro, HNECs stimulated with RWE increased indistinctively the production of pro‐inflammatory cytokines (IL‐8, IL‐1β, and IL‐6). In contrast, supernatants from CO₂‐RWE‐stimulated HNECs, compared to control‐RWE‐stimulated HNECS, significantly increased TNF and decreased IL‐10 production in DCs. Comparable results were obtained by stimulating DCs directly with RWEs. The metabolome analysis revealed differential expression of secondary plant metabolites in control‐ vs CO₂‐RWE. Mixes of these metabolites elicited similar responses in DCs as compared to respective RWEs.Conclusion: Our results indicate that elevated ambient CO₂ levels elicit a stronger RWE‐induced allergic response in vivo and in vitro and that RWE increased allergenicity depends on the interplay of multiple metabolites.

One of the most intriguing features of the brain is its ability to be malleable, allowing it to adapt continually to changes in the environment. Specific neuronal activity patterns drive long‐lasting increases or decreases in the strength of synaptic connections, referred to as long‐term potentiation and long‐term depression, respectively. Such phenomena have been described in a variety of model organisms, which are used to study molecular, structural, and functional aspects of synaptic plasticity. This review originated from the first International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Alpbach, Austria (Sep 2016), and will use its curriculum and discussions as a framework to review some of the current knowledge in the field of synaptic plasticity. First, we describe the role of plasticity during development and the persistent changes of neural circuitry occurring when sensory input is altered during critical developmental stages. We then outline the signaling cascades resulting in the synthesis of new plasticity‐related proteins, which ultimately enable sustained changes in synaptic strength. Going beyond the traditional understanding of synaptic plasticity conceptualized by long‐term potentiation and long‐term depression, we discuss system‐wide modifications and recently unveiled homeostatic mechanisms, such as synaptic scaling. Finally, we describe the neural circuits and synaptic plasticity mechanisms driving associative memory and motor learning. Evidence summarized in this review provides a current view of synaptic plasticity in its various forms, offers new insights into the underlying mechanisms and behavioral relevance, and provides directions for future research in the field of synaptic plasticity. image Read the Editorial Highlight for this article on page 788.Cover Image for this issue: doi: 10.1111/jnc.13815.

Matrix metalloproteinase 9 (MMP‐9) has recently emerged as a molecule that contributes to pathological synaptic plasticity in schizophrenia, but explanation of the underlying mechanisms has been missing. In the present study, we performed a phenotype‐based genetic association study (PGAS) in > 1,000 schizophrenia patients from the Göttingen Research Association for Schizophrenia (GRAS) data collection and found an association between the MMP‐9 rs20544 C/T single‐nucleotide polymorphism (SNP) located in the 3′untranslated region (UTR) and the severity of a chronic delusional syndrome. In cultured neurons, the rs20544 SNP influenced synaptic MMP‐9 activity and the morphology of dendritic spines. We demonstrated that Fragile X mental retardation protein (FMRP) bound the MMP‐9 3′UTR. We also found dramatic changes in RNA structure folding and alterations in the affinity of FMRP for MMP‐9 RNA, depending on the SNP variant. Finally, we observed greater sensitivity to psychosis‐related locomotor hyperactivity in Mmp‐9 heterozygous mice. We propose a novel mechanism that involves MMP‐9‐dependent changes in dendritic spine morphology and the pathophysiology of schizophrenia, providing the first mechanistic insights into the way in which the single base change in the MMP‐9 gene (rs20544) influences gene function and results in phenotypic changes observed in schizophrenia patients. Synopsis A single‐nucleotide polymorphism rs20544 located in the 3′ untranslated region of the MMP‐9 gene modulates synaptic MMP‐9 protein levels and contributes significantly to the chronic delusional syndrome in schizophrenia patients. rs20544 MMP‐9 gene polymorphism markedly affects delusional symptoms in schizophrenic patients, without influencing overall susceptibility to the disease. rs20544 polymorphism influences synaptic MMP‐9 activity and the morphology of dendritic spines. rs20544 polymorphism affects MMP‐9 mRNA structure and the affinity of FMRP binding to MMP‐9 mRNA. lower levels of MMP‐9 in the brain in Mmp‐9 heterozygous mice resulted in greater sensitivity to psychosis‐related locomotor hyperactivity.