Inhibition of colony stimulating factor 1 receptor corrects maternal inflammation-induced microglial and synaptic dysfunction and behavioral abnormalities.

Maternal immune activation (MIA) disrupts the central innate immune system during a critical neurodevelopmental period. Microglia are primary innate immune cells in the brain although their direct influence on the MIA phenotype is largely unknown. Here we show that MIA alters microglial gene expression with upregulation of cellular protrusion/neuritogenic pathways, concurrently causing repetitive behavior, social deficits, and synaptic dysfunction to layer V intrinsically bursting pyramidal neurons in the prefrontal cortex of mice. MIA increases plastic dendritic spines of the intrinsically bursting neurons and their interaction with hyper-ramified microglia. Treating MIA offspring by colony stimulating factor 1 receptor inhibitors induces depletion and repopulation of microglia, and corrects protein expression of the newly identified MIA-associated neuritogenic molecules in microglia, which coalesces with correction of MIA-associated synaptic, neurophysiological, and behavioral abnormalities. Our study demonstrates that maternal immune insults perturb microglial phenotypes and influence neuronal functions throughout adulthood, and reveals a potent effect of colony stimulating factor 1 receptor inhibitors on the correction of MIA-associated microglial, synaptic, and neurobehavioral dysfunctions.

I saw the swirl sign: Acute extravasation of blood within a hematoma.

The swirl sign is a finding on non-contrast computed tomography (CT) scans that represents an acute extravasation of blood into a hematoma filled with clotted blood. In it, a "swirl" of active bleeding within a body of acutely clotted blood is noted as a hypodense accumulation within a hyperdense fluid collection. Here, we describe a case in which a 35-year-old female presents unresponsive with a Glasgow Coma Scale score of 3 and is ultimately found to have a large frontal intraparenchymal hematoma with intraventricular extension and an area of low attenuation within the hyperattenuating fluid collection on CT, otherwise known as the swirl sign. This radiographic sign has been associated with hematoma expansion, worse clinical outcomes as measured by the Glasgow Outcome Scale, and higher mortality rates. As such, all patients suspected to have intracranial bleeds should have CT imaging done as soon as possible. When the swirl sign is identified on CT, providers are clued in to the risk of clinical deterioration and the urgent need for surgical evaluation.

Neuroimmune Crosstalk through Extracellular Vesicles in Health and Disease.

The dynamics of CNS function rely upon omnidirectional communication among CNS cell types. Extracellular vesicles (EVs) have emerged as key mediators of this communication and are actively involved in response to CNS injury, mediating inflammatory response and inflammation-related neuroprotection as they display dual beneficial and detrimental roles. Neuroimmune interactions include communication between neurons and microglia, the resident macrophages within the CNS, and these interactions are a critical mediator of healthy brain functions, mounting an inflammatory response, and disease pathogenesis. This review aims to organize recent research highlighting the role of EVs in health and neurodegenerative disorders, with a specific focus on neuroimmune interactions between neurons and glia in Alzheimer's disease.

Cre-inducible Adeno Associated Virus-mediated Expression of P301L Mutant Tau Causes Motor Deficits and Neuronal Degeneration in the Substantia Nigra.

Accumulation of microtubule associated protein tau in the substantia nigra is associated with several tauopathies including progressive supranuclear palsy (PSP). A number of studies have used mutant tau transgenic mouse model to mimic the neuropathology of tauopathies and disease phenotypes. However, tau expression in these transgenic mouse models is not specific to brain subregions, and may not recapitulate subcortical disease phenotypes of PSP. It is necessary to develop a new disease modeling system for cell and region-specific expression of pathogenic tau for modeling PSP in mouse brain. In this study, we developed a novel strategy to express P301L mutant tau to the dopaminergic neurons of substantia nigra by coupling tyrosine hydroxylase promoter Cre-driver mice with a Cre-inducible adeno-associated virus (iAAV). The results showed that P301L mutant tau was successfully transduced in the dopaminergic neurons of the substantia nigra at the presence of Cre recombinase and iAAV. Furthermore, the iAAV-tau-injected mice displayed severe motor deficits including impaired movement ability, motor balance, and motor coordination compared to the control groups over a short time-course. Immunochemical analysis revealed that tau gene transfer significantly resulted in loss of tyrosine hydroxylase-positive dopaminergic neurons and elevated phosphorylated tau in the substantia nigra. Our development of dopaminergic neuron-specific neurodegenerative mouse model with tauopathy will be helpful for studying the underlying mechanism of pathological protein propagation as well as development of new therapies.