N-methyl-D-aspartate receptor (NMDAR) excitotoxicity is implicated in the pathogenesis of Huntington's disease (HD), a late-onset neurodegenerative disorder. However, NMDARs are poor therapeutic targets, due to their essential physiological role. Recent studies demonstrate that synaptic NMDAR transmission drives neuroprotective gene transcription, whereas extrasynaptic NMDAR activation promotes cell death. We report specifically increased extrasynaptic NMDAR expression, current, and associated reductions in nuclear CREB activation in HD mouse striatum. The changes are observed in the absence of dendritic morphological alterations, before and after phenotype onset, correlate with mutation severity, and require caspase-6 cleavage of mutant huntingtin. Moreover, pharmacological block of extrasynaptic NMDARs with memantine reversed signaling and motor learning deficits. Our data demonstrate elevated extrasynaptic NMDAR activity in an animal model of neurodegenerative disease. We provide a candidate mechanism linking several pathways previously implicated in HD pathogenesis and demonstrate successful early therapeutic intervention in mice.

The following is the corrected Acknowledgments section, which includes funding information that was missing from the previous version.

Complement receptor 3 (CR3) activation in microglia is involved in neuroinflammation-related brain disorders and pruning of neuronal synapses. Hypoxia, often observed together with neuroinflammation in brain trauma, stroke, and neurodegenerative diseases, is thought to exacerbate inflammatory responses and synergistically enhance brain damage. Here we show that when hypoxia and an inflammatory stimulus (lipopolysaccharide [LPS]) are combined, they act synergistically to trigger long-term synaptic depression (LTD) that requires microglial CR3, activation of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), and GluA2-mediated A-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization. Microglial CR3-triggered LTD is independent of N-methyl-D-aspartate receptors (NMDARs), metabotropic glutamate receptors (mGluRs), or patterned synaptic activity. This type of LTD may contribute to memory impairments and synaptic disruptions in neuroinflammation-related brain disorders.

Astrocytes display complex morphologies with an array of fine extensions extending from the soma and the primary thick processes. Until the use of genetically encoded calcium indicators (GECIs) selectively expressed in astrocytes, Ca signaling was only examined in soma and thick primary processes of astrocytes where Ca -sensitive fluorescent dyes could be imaged. GECI imaging in astrocytes revealed a previously unsuspected pattern of spontaneous Ca transients in fine processes that has not been observed without chronic expression of GECIs, raising potential concerns about the effects of GECI expression. Here, we perform two-photon imaging of Ca transients in adult CA1 hippocampal astrocytes using a new single-cell patch-loading strategy to image Ca -sensitive fluorescent dyes in the cytoplasm of fine processes. We observed that astrocyte fine processes exhibited a high frequency of spontaneous Ca transients whereas astrocyte soma rarely showed spontaneous Ca oscillations similar to previous reports using GECIs. We exploited this new approach to show these signals were independent of neuronal spiking, metabotropic glutamate receptor (mGluR) activity, TRPA1 channels, and L- or T-type voltage-gated calcium channels. Removal of extracellular Ca almost completely and reversibly abolished the spontaneous signals while IP R2 KO mice also exhibited spontaneous and compartmentalized signals, suggesting they rely on influx of extracellular Ca . The Ca influx dependency of the spontaneous signals in patch-loaded astrocytes was also observed in astrocytes expressing GCaMP3, further highlighting the presence of Ca influx pathways in astrocytes. The mechanisms underlying these localized Ca signals are critical for understanding how astrocytes regulate important functions in the adult brain. GLIA 2016;64:2093-2103.

Using a diagnostically heterogeneous outpatient population, this study is, we believe, the first to report that persistent antipsychotic polypharmacy is associated with excessive dosing, in and of itself as well as compared to antipsychotic monotherapy.