Members of the extended interleukin-1 (IL-1) cytokine family, such as IL-1, IL-18, IL-33, and IL-36, play a pivotal role in the initiation and amplification of immune responses. However, deregulated production and/or activation of these cytokines can lead to the development of multiple inflammatory disorders. IL-1 family members share a broadly similar domain organization and receptor signaling pathways. Another striking similarity between IL-1 family members is the requirement for proteolytic processing in order to unlock their full biological potential. Although much emphasis has been put on the role of caspase-1, another emerging theme is the involvement of neutrophil- and mast cell-derived proteases in IL-1 family cytokine processing. Elucidating the regulation of IL-1 family members by proteolytic processing is of great interest for understanding inflammation and immunity. Here, we review the identity of the proteases involved in the proteolytic processing of IL-1 family cytokines and the therapeutic implications in inflammatory disease.

The transformation of dendritic excitatory synaptic inputs to axonal action potential output is the fundamental computation performed by all principal neurons. We show that in the hippocampus this transformation is potently controlled by recurrent inhibitory microcircuits. However, excitatory input on highly excitable dendritic branches could resist inhibitory control by generating strong dendritic spikes and trigger precisely timed action potential output. Furthermore, we show that inhibition-sensitive branches can be transformed into inhibition-resistant, strongly spiking branches by intrinsic plasticity of branch excitability. In addition, we demonstrate that the inhibitory control of spatially defined dendritic excitation is strongly regulated by network activity patterns. Our findings suggest that dendritic spikes may serve to transform correlated branch input into reliable and temporally precise output even in the presence of inhibition.

In the central nervous system (CNS) of most vertebrates, oligodendrocytes enwrap neuronal axons with extensions of their plasma membrane to form the myelin sheath. Several proteins are characteristically found in myelin of which myelin basic protein (MBP) is the second most abundant one after proteolipid protein. The lack of functional MBP in rodents results in a severe hypomyelinated phenotype in the CNS demonstrating its importance for myelin synthesis. Mbp mRNA is transported from the nucleus to the plasma membrane and is translated locally at the axon–glial contact site. Axonal properties such as diameter or electrical activity influence the degree of myelination. As oligodendrocytes can myelinate many axonal segments with varying properties, localized MBP translation represents an important part of a rapid and axon-tailored synthesis machinery. MBP’s ability to compact cellular membranes may be problematic for the integrity of intracellular membranous organelles and can also explain why MBP is transported in oligodendrocytes in the form of an mRNA rather than as a protein. Here we review the recent findings regarding intracellular transport and signaling mechanisms leading to localized translation of Mbp mRNA in oligodendrocytes. More detailed insights into the MBP synthesis pathway are important for a better understanding of the myelination process and may foster the development of remyelination therapies for demyelinating diseases.

The septo–hippocampal pathway adjusts CA1 network excitability to different behavioral states and is crucially involved in theta rhythmogenesis. In the medial septum, cholinergic, glutamatergic and GABAergic neurons form a highly interconnected local network. Neurons of these three classes project to glutamatergic pyramidal neurons and different subsets of GABAergic neurons in the hippocampal CA1 region. From there, GABAergic neurons project back to the medial septum and form a feedback loop between the two remote brain areas. In vivo, the firing of GABAergic medial septal neurons is theta modulated, while theta modulation is not observed in cholinergic neurons. One prominent feature of glutamatergic neurons is the correlation of their firing rates to the animals running speed. The cellular diversity, the high local interconnectivity and different activity patterns of medial septal neurons during different behaviors complicate the functional dissection of this network. New technical advances help to define specific functions of individual cell classes. In this review, we seek to highlight recent findings and elucidate functional implications of the septo-hippocampal connectivity on the microcircuit scale.

In the CA1 region of the hippocampus pyramidal neurons and GABAergic interneurons form local microcircuits. CA1 interneurons are a diverse group consisting of many subtypes, some of which provide compartment-specific inhibition specifically onto pyramidal neuron dendrites. In fact, the majority of inhibitory synapses on pyramidal neurons is found on their dendrites. The specific role of a dendrite-innervating interneuron subtype is primarily determined by its innervation pattern on the distinct dendritic domains of pyramidal neurons. The efficacy of dendritic inhibition in reducing dendritic excitation depends on the relative timing and location of the activated excitatory and inhibitory synapses. In vivo, synaptic properties such as short-term plasticity and neuro-modulation by the basal forebrain, govern the degree of inhibition in distinct dendritic domains in a dynamic, behavior dependent manner, specifically during network oscillation such as the theta rhythm. In this review we focus on two subtypes of dendrite-innervating interneurons: the oriens-lacunosum moleculare (O-LM) interneuron and the bistratified interneuron. Their molecular marker profile, morphology, and function in vivo and in vitro are well studied. We strive to integrate this diverse information from the cellular to the network level, and to provide insight into how the different characteristics of O-LM and bistratified interneurons affect dendritic excitability, network activity, and behavior.

Rapid nerve conduction in the CNS is facilitated by insulation of axons with myelin, a specialized oligodendroglial compartment distant from the cell body. Myelin is turned over and adapted throughout life; however, the molecular and cellular basis of myelin dynamics remains elusive. Here we performed a comprehensive transcriptome analysis (RNA-seq) of myelin biochemically purified from mouse brains at various ages and find a surprisingly large pool of transcripts enriched in myelin. Further computational analysis showed that the myelin transcriptome is closely related to the myelin proteome but clearly distinct from the transcriptomes of oligodendrocytes and brain tissues, suggesting a highly selective incorporation of mRNAs into the myelin compartment. The mRNA-pool in myelin displays maturation-dependent dynamic changes of composition, abundance, and functional associations; however ageing-dependent changes after 6 months were minor. We suggest that this transcript pool enables myelin turnover and the local adaptation of individual pre-existing myelin sheaths.

Neurons extend long axons that require maintenance and are susceptible to degeneration. Long-term integrity of axons depends on intrinsic mechanisms including axonal transport and extrinsic support from adjacent glial cells. The mechanisms of support provided by myelinating oligodendrocytes to underlying axons are only partly understood. Oligodendrocytes release extracellular vesicles (EVs) with properties of exosomes, which upon delivery to neurons improve neuronal viability in vitro. Here, we show that oligodendroglial exosome secretion is impaired in 2 mouse mutants exhibiting secondary axonal degeneration due to oligodendrocyte-specific gene defects. Wild-type oligodendroglial exosomes support neurons by improving the metabolic state and promoting axonal transport in nutrient-deprived neurons. Mutant oligodendrocytes release fewer exosomes, which share a common signature of underrepresented proteins. Notably, mutant exosomes lack the ability to support nutrient-deprived neurons and to promote axonal transport. Together, these findings indicate that glia-to-neuron exosome transfer promotes neuronal long-term maintenance by facilitating axonal transport, providing a novel mechanistic link between myelin diseases and secondary loss of axonal integrity.

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