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Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin gene. Major pathological hallmarks of HD include inclusions of mutant huntingtin (mHTT) protein, loss of neurons predominantly in the caudate nucleus, and atrophy of multiple brain regions. However, the early sequence of histological events that manifest in region- and cell-specific manner has not been well characterized. Here we use a high-content histological approach to precisely monitor changes in HTT expression and characterize deposition dynamics of mHTT protein inclusion bodies in the recently characterized zQ175 knock-in mouse line. We carried out an automated multi-parameter quantitative analysis of individual cortical and striatal cells in tissue slices from mice aged 2–12 months and confirmed biochemical reports of an age-associated increase in mHTT inclusions in this model. We also found distinct regional and subregional dynamics for inclusion number, size and distribution with subcellular resolution. We used viral-mediated suppression of total HTT in the striatum of zQ175 mice as an example of a therapeutically-relevant but heterogeneously transducing strategy to demonstrate successful application of this platform to quantitatively assess target engagement and outcome on a cellular basis. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia is a complex neurodevelopmental disorder. Patients typically start exhibiting symptoms during adolescence, coinciding with a critical period for the maturation of the prefrontal cortex. While previous studies have identified deficits in cortical interneuron integrity and network function in chronic patients, little is known about the maladaptive circuitry in the early prodromal phase of the disease. To assess pathophysiological changes during adolescence that might contribute to the disruption of cortical network function we have studied a 15q13.3 microdeletion mouse model Df[h15q13]−/+ resembling a human copy number variant (CNV) known to confer high risk for psychiatric disorders such as schizophrenia. Using a combination of histology, in vitro electrophysiology and electroencephalography (EEG) we explored the interneuronal connectivity and cortical network functionality in the Df[h15q13]−/+ mouse model from adolescence to early adulthood Methods: Immunohistological analysis was performed on brain slices within the prefrontal cortex, dorsal hippocampus and amygdala region from Df[h15q13]−/+ and wild-type mice (N=8) at PND35 and PND70 (4 sections/brain). Sections were immunostained for markers of interneuron subtypes and respective synapses. Fluorescence images were recorded and processed with an Opera Phenix (PerkinElmer) using the 63x objective in confocal mode. EEG studies were performed on Df[h15q13]−/+ and wild-type mice within the age range of PND41 to PND70 (6). Mice were obtained from Taconic and housed within the experimental facility for at least one week prior to experimental procedures. Results: We initially confirmed that the adult Df[h15q13]−/+ microdeletion mouse model exhibits robust markers reminiscent of schizophrenialinked pathology, such as the reduction of parvalbumin positive (PV+) interneurons, lower abundance of perineuronal net proteins (PNNs) and an impaired cortical processing of sensory information. We identified abnormalities in the number and distribution of interneuron synapses in the prefrontal cortex, hippocampus and amygdala, the phenotype in the adolescent brain, which were opposed to pathophysiological changes identified in adult Df[h15q13]−/+ microdeletion mice. We discovered an enhanced inhibitory drive from specific subpopulations of interneurons during adolescence that might contribute to deficits in the adult hippocampal and PFC network. Likewise, we found Df[h15q13]−/+ specific differences in cortical network processing between adolescent and adult mice revealed by EEG. To align the development of cortical network function to the progressive changes in network structure we performed longitudinal EEG recordings and uncovered particular abnormalities in basal and evoked oscillatory rhythms in adolescent and adult mice. Discussion: In this study, we discovered abnormalities in the interneuron integration during a critical period for the maturation of the prefrontal cortex in a 15q13.3 microdeletion mouse model. Our findings provide novel insights into early deficits in the limbic and cortical neuronal networks that may drive circuit dysfunction in schizophrenia patients. Identification of adolescent pathophysiology in models for schizophrenia risk will provide the opportunity to explore new mechanisms for early intervention. [ABSTRACT FROM AUTHOR]

Overeating disorders largely contribute to worldwide incidences of obesity. Available treatments are limited. Here, we discovered that long-term chemogenetic activation of ventrolateral periaqueductal gray (vlPAG) GABAergic cells rescue obesity of high-fat diet-induced obesity (DIO) mice. Thiswas associated with the recovery of enhanced mIPSCs, decreased food intake, increased energy expenditure, and inguinal white adipose tissue (iWAT) browning. In vivo calcium imaging confirmed vlPAG GABAergic suppression for DIO mice, with corresponding reduction in intrinsic excitability. Single-nucleus RNA sequencing identified transcriptional expression changes in GABAergic cell subtypes in DIO mice, highlighting Cacna2d1 as of potential importance. Overexpressing CACNA2D1 in vlPAG GABAergic cells of DIO mice rescued enhanced mIPSCs and calcium response, reversed obesity, and therefore presented here as a potential target for obesity treatment. [ABSTRACT FROM AUTHOR]

Overeating disorders largely contribute to worldwide incidences of obesity. Available treatments are limited. Here, we discovered that long-term chemogenetic activation of ventrolateral periaqueductal gray (vlPAG) GABAergic cells rescue obesity of high-fat diet-induced obesity (DIO) mice. This was associated with the recovery of enhanced mIPSCs, decreased food intake, increased energy expenditure, and inguinal white adipose tissue (iWAT) browning. In vivo calcium imaging confirmed vlPAG GABAergic suppression for DIO mice, with corresponding reduction in intrinsic excitability. Single-nucleus RNA sequencing identified transcriptional expression changes in GABAergic cell subtypes in DIO mice, highlighting Cacna2d1 as of potential importance. Overexpressing CACNA2D1 in vlPAG GABAergic cells of DIO mice rescued enhanced mIPSCs and calcium response, reversed obesity, and therefore presented here as a potential target for obesity treatment.

Lateral diffusion on the neuronal plasma membrane of the AMPA-type glutamate receptor (AMPAR) serves an important role in synaptic plasticity. We investigated the role of the secreted glycoprotein Noelin1 (Olfactomedin-1 or Pancortin) in AMPAR lateral mobility and its dependence on the extracellular matrix (ECM). We found that Noelin1 interacts with the AMPAR with high affinity, however, without affecting rise- and decay time and desensitization properties. Noelin1 co-localizes with synaptic and extra-synaptic AMPARs and is expressed at synapses in an activity-dependent manner. Single-particle tracking shows that Noelin1 reduces lateral mobility of both synaptic and extra-synaptic GluA1-containing receptors and affects short-term plasticity. While the ECM does not constrain the synaptic pool of AMPARs and acts only extrasynaptically, Noelin1 contributes to synaptic potentiation by limiting AMPAR mobility at synaptic sites. This is the first evidence for the role of a secreted AMPAR-interacting protein on mobility of GluA1-containing receptors and synaptic plasticity., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)