Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity.

Synapse remodeling is essential to encode experiences into neuronal circuits. Here, we define a molecular interaction between neurons and microglia that drives experience-dependent synapse remodeling in the hippocampus. We find that the cytokine interleukin-33 (IL-33) is expressed by adult hippocampal neurons in an experience-dependent manner and defines a neuronal subset primed for synaptic plasticity. Loss of neuronal IL-33 or the microglial IL-33 receptor leads to impaired spine plasticity, reduced newborn neuron integration, and diminished precision of remote fear memories. Memory precision and neuronal IL-33 are decreased in aged mice, and IL-33 gain of function mitigates age-related decreases in spine plasticity. We find that neuronal IL-33 instructs microglial engulfment of the extracellular matrix (ECM) and that its loss leads to impaired ECM engulfment and a concomitant accumulation of ECM proteins in contact with synapses. These data define a cellular mechanism through which microglia regulate experience-dependent synapse remodeling and promote memory consolidation.

Astrocyte-immune cell interactions in physiology and pathology.

Astrocytes play both physiological and pathological roles in maintaining central nervous system (CNS) function. Here, we review the varied functions of astrocytes and how these might change in subsets of reactive astrocytes. We review the current understanding of astrocyte interactions with microglia and the vasculature and protective barriers in the central nervous system as well as highlight recent insights into physiologic and reactive astrocyte sub-states identified by transcriptional profiling. Our goal is to stimulate inquiry into how these molecular identifiers link to specific functional changes in astrocytes and to define the implications of these heterogeneous molecular and functional changes in brain function and pathology. Defining these complex interactions has the potential to yield new therapies in CNS injury, infection, and disease.

Cargo specificity, regulation, and therapeutic potential of cytoplasmic dynein.

Intracellular retrograde transport in eukaryotic cells relies exclusively on the molecular motor cytoplasmic dynein 1. Unlike its counterpart, kinesin, dynein has a single isoform, which raises questions about its cargo specificity and regulatory mechanisms. The precision of dynein-mediated cargo transport is governed by a multitude of factors, including temperature, phosphorylation, the microtubule track, and interactions with a family of activating adaptor proteins. Activating adaptors are of particular importance because they not only activate the unidirectional motility of the motor but also connect a diverse array of cargoes with the dynein motor. Therefore, it is unsurprising that dysregulation of the dynein-activating adaptor transport machinery can lead to diseases such as spinal muscular atrophy, lower extremity, and dominant. Here, we discuss dynein motor motility within cells and in in vitro, and we present several methodologies employed to track the motion of the motor. We highlight several newly identified activating adaptors and their roles in regulating dynein. Finally, we explore the potential therapeutic applications of manipulating dynein transport to address diseases linked to dynein malfunction.

Microglial pattern recognition via IL-33 promotes synaptic refinement in developing corticothalamic circuits in mice.

Microglia are critical regulators of brain development that engulf synaptic proteins during postnatal synapse remodeling. However, the mechanisms through which microglia sense the brain environment are not well defined. Here, we characterized the regulatory program downstream of interleukin-33 (IL-33), a cytokine that promotes microglial synapse remodeling. Exposing the developing brain to a supraphysiological dose of IL-33 altered the microglial enhancer landscape and increased binding of stimulus-dependent transcription factors including AP-1/FOS. This induced a gene expression program enriched for the expression of pattern recognition receptors, including the scavenger receptor MARCO. CNS-specific deletion of IL-33 led to increased excitatory/inhibitory synaptic balance, spontaneous absence-like epileptiform activity in juvenile mice, and increased seizure susceptibility in response to chemoconvulsants. We found that MARCO promoted synapse engulfment, and Marco-deficient animals had excess thalamic excitatory synapses and increased seizure susceptibility. Taken together, these data define coordinated epigenetic and functional changes in microglia and uncover pattern recognition receptors as potential regulators of postnatal synaptic refinement.

Long-Term Isolation Elicits Depression and Anxiety-Related Behaviors by Reducing Oxytocin-Induced GABAergic Transmission in Central Amygdala.

Isolation stress is a major risk factor for neuropsychiatric disorders such as depressive and anxiety disorders. However, the molecular mechanisms underlying isolation-induced neuropsychiatric disorders remain elusive. In the present study, we investigated the subcellular mechanisms by which long-term isolation elicits depression and anxiety-related behaviors in mice. First, we found that long-term isolation induced depression-related behaviors in the forced swimming test (FST) and the sucrose preference test, as well as anxiety-related behaviors in the elevated zero maze test (EZMT) and the open field test. Next, we showed that intracentral amygdala (CeA) injection of oxytocin (OXT), but not intracerebroventricular injection, attenuated isolation-induced depression and anxiety-related behaviors via oxytocin receptor (OXTR), not vasopressin-1a receptor (V1aR), in the FST and EZMT, respectively. Quantitative real-time polymerase chain reaction analysis revealed that after 5 weeks of isolation, mRNA transcription of OXTR in the CeA, but not that of V1aR, significantly decreased, whereas OXT and vasopressin mRNA transcription in the paraventricular nucleus of hypothalamus did not change significantly. Whole-cell patch clamping of acute brain slices demonstrated that the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in CeA neurons, but not their amplitude, was lower in isolated mice than in group-housed mice. Notably, OXT treatment increased the mIPSC frequency in the CeA neurons, but to a lesser extent in the case of isolated mice than in that of group-housed mice via OXTR. Taken together, our findings suggest that long-term isolation down-regulates OXTR mRNA transcription and diminishes OXT-induced inhibitory synaptic transmission in the CeA and may contribute to the development of depression and anxiety-related behaviors in isolated mice through the enhancement of CeA activity.