GABA-receptive microglia selectively sculpt developing inhibitory circuits.

Microglia, the resident immune cells of the brain, have emerged as crucial regulators of synaptic refinement and brain wiring. However, whether the remodeling of distinct synapse types during development is mediated by specialized microglia is unknown. Here, we show that GABA-receptive microglia selectively interact with inhibitory cortical synapses during a critical window of mouse postnatal development. GABA initiates a transcriptional synapse remodeling program within these specialized microglia, which in turn sculpt inhibitory connectivity without impacting excitatory synapses. Ablation of GABAB receptors within microglia impairs this process and leads to behavioral abnormalities. These findings demonstrate that brain wiring relies on the selective communication between matched neuronal and glial cell types.

Gene augmentation therapy to rescue degenerative photoreceptors in a Cwc27 mutant mouse model.

Previous reports have demonstrated that defects in the spliceosome-associated protein CWC27 can lead to the degeneration of retinal cells in Cwc27 mutant mouse models. However, it is unknown whether gene replacement therapy can rescue this phenotype. The purpose of this study was to evaluate whether AAV based gene therapy could rescue the retinal degeneration observed in Cwc27 mutant mice. By 6 months of age, Cwc27 mutant mice show a retinal degenerative phenotype, including morphological and functional abnormalities, primarily driven by the death of photoreceptors. We hypothesize that subretinal injection of AAV8 to drive exogenous CWC27 protein expression will improve the retinal phenotype. We evaluated these improvements after gene therapy with electroretinography (ERG) and histology, either hematoxylin and eosin (H&E) or immunostaining. In this study, we demonstrated that subretinal injection of AAV8-GRK-Cwc27-FLAG in mutant mice can improve the functionality and morphology of the retina. Immunostaining analyses revealed a notable decrease in photoreceptor degeneration, including cone cell degeneration, in the AAV-injected eyes compared to the PBS-injected eyes. Based on these results, gene replacement therapy could be a promising method for treating retinal degeneration caused by mutations in Cwc27.

A Mutation in Hnrnph1 That Decreases Methamphetamine-Induced Reinforcement, Reward, and Dopamine Release and Increases Synaptosomal hnRNP H and Mitochondrial Proteins.

Individual variation in the addiction liability of amphetamines has a heritable genetic component. We previously identified Hnrnph1 (heterogeneous nuclear ribonucleoprotein H1) as a quantitative trait gene underlying decreased methamphetamine-induced locomotor activity in mice. Here, we showed that mice (both females and males) with a heterozygous mutation in the first coding exon of Hnrnph1 (H1+/-) showed reduced methamphetamine reinforcement and intake and dose-dependent changes in methamphetamine reward as measured via conditioned place preference. Furthermore, H1+/- mice showed a robust decrease in methamphetamine-induced dopamine release in the NAc with no change in baseline extracellular dopamine, striatal whole-tissue dopamine, dopamine transporter protein, dopamine uptake, or striatal methamphetamine and amphetamine metabolite levels. Immunohistochemical and immunoblot staining of midbrain dopaminergic neurons and their forebrain projections for TH did not reveal any major changes in staining intensity, cell number, or forebrain puncta counts. Surprisingly, there was a twofold increase in hnRNP H protein in the striatal synaptosome of H1+/- mice with no change in whole-tissue levels. To gain insight into the mechanisms linking increased synaptic hnRNP H with decreased methamphetamine-induced dopamine release and behaviors, synaptosomal proteomic analysis identified an increased baseline abundance of several mitochondrial complex I and V proteins that rapidly decreased at 30 min after methamphetamine administration in H1+/- mice. In contrast, the much lower level of basal synaptosomal mitochondrial proteins in WT mice showed a rapid increase. We conclude that H1+/- decreases methamphetamine-induced dopamine release, reward, and reinforcement and induces dynamic changes in basal and methamphetamine-induced synaptic mitochondrial function.SIGNIFICANCE STATEMENT Methamphetamine dependence is a significant public health concern with no FDA-approved treatment. We discovered a role for the RNA binding protein hnRNP H in methamphetamine reward and reinforcement. Hnrnph1 mutation also blunted methamphetamine-induced dopamine release in the NAc, a key neurochemical event contributing to methamphetamine addiction liability. Finally, Hnrnph1 mutants showed a marked increase in basal level of synaptosomal hnRNP H and mitochondrial proteins that decreased in response to methamphetamine, whereas WT mice showed a methamphetamine-induced increase in synaptosomal mitochondrial proteins. Thus, we identified a potential role for hnRNP H in basal and dynamic mitochondrial function that informs methamphetamine-induced cellular adaptations associated with reduced addiction liability.

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia: Imaging and Clinical Features of a Frequently Delayed Diagnosis.

OBJECTIVE. The purpose of this study was to assess features of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) on CT, clinical presentation, and delays in radiologic and clinical diagnosis in a series of 32 patients. MATERIALS AND METHODS. Medical records of patients with DIPNECH from the years 2000-2017 were obtained from an institutional data warehouse. Inclusion criteria were an available CT examination and either a pathologic diagnosis of DIPNECH or pathologic findings of multiple carcinoid tumorlets or carcinoid tumor with CT features suggesting DIPNECH. Two thoracic radiologists with 10 and 14 years of experience reviewed CT examinations and scored cases in consensus. RESULTS. All 32 patients were women, and most had never smoked (69%). The mean age at presentation was 61 years. Symptoms included chronic cough (59%) or dyspnea (28%), and the initial clinical diagnosis was asthma in 41%. DIPNECH was clinically suspected at presentation in only one case and was mentioned by the interpreting radiologist in only 31% of cases. CT characteristics included numerous nodules with a lower zone and peribronchiolar predominance, mosaic attenuation, and nodular bronchial wall thickening. Number of nodules at least 5 mm in diameter showed strong inverse correlations with the percentage predicted for both forced vital capacity and forced expiratory volume in 1 second and a moderate inverse correlation with total lung capacity percentage predicted. In cases with a follow-up CT interval of 3 years or longer, 85% of patients showed an increase in size of the largest nodule, and 70% had an increase in size in multiple nodules. CONCLUSION. Many cases of DIPNECH are originally missed or misdiagnosed by radiologists and clinicians. Awareness of the typical clinical and imaging features of DIPNECH may prompt earlier diagnosis of this condition.

Quantitative susceptibility mapping of the motor cortex in amyotrophic lateral sclerosis and primary lateral sclerosis.

OBJECTIVE: The diagnosis of amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) is often difficult because of a lack of disease biomarkers. The purpose of this study was to investigate quantitative susceptibility mapping (QSM) of the motor cortex as a potential quantitative biomarker for the diagnosis of ALS and PLS. MATERIALS AND METHODS: From a retrospective database, QSM images of 16 patients with upper motor neuron disease (nine men [56%], seven women; mean age, 56.3 years; 12 with ALS, four with PLS) and 23 control patients (13 men [56%], 10 women; mean age, 56.6 years) were reviewed. Two neuroradiologists, blinded to diagnosis, qualitatively assessed QSM, T2- and T2*-weighted, and T2-weighted FLAIR images. Relative motor cortex susceptibility was calculated by subtraction of adjacent white matter and CSF signal intensity from mean motor cortex susceptibility on the axial image most representative of the right- or left-hand lobule, and ROC analysis was performed. The Fisher exact and Student t tests were used to evaluate for statistical differences between the groups. RESULTS: Qualitatively, QSM had greater diagnostic accuracy than T2-weighted, T2*-weighted, or T2-weighted FLAIR imaging for the diagnosis of ALS and PLS. Quantitatively, relative motor cortex susceptibility was found to be significantly greater in patients with motor neuron disease than in control patients (46.0 and 35.0 ppb; p < 0.001). ROC analysis showed an AUC of 0.88 (p < 0.0001) and an optimal cutoff value of 40.5 ppb for differentiating control patients from patients with ALS or PLS (sensitivity, 87.5%; specificity, 87.0%). CONCLUSION: QSM is a sensitive and specific quantitative biomarker of iron deposition in the motor cortex in ALS and PLS.

Changes in neuronal immunofluorescence in the C- versus N-terminal domains of hnRNP H following D1 dopamine receptor activation.

RNA binding proteins are a diverse class of proteins that regulate all aspects of RNA metabolism. Accumulating studies indicate that heterogeneous nuclear ribonucleoproteins are associated with cellular adaptations in response to drugs of abuse. We recently mapped and validated heterogeneous nuclear ribonucleoprotein H1 (Hnrnph1) as a quantitative trait gene underlying differential behavioral sensitivity to methamphetamine. The molecular mechanisms by which hnRNP H1 alters methamphetamine behaviors are unknown but could involve pre- and/or post-synaptic changes in protein localization and function. Methamphetamine initiates post-synaptic D1 dopamine receptor signaling indirectly by binding to pre-synaptic dopamine transporters and vesicular monoamine transporters of midbrain dopaminergic neurons which triggers reverse transport and accumulation of dopamine at the synapse. Here, we examined changes in neuronal localization of hnRNP H in primary rat cortical neurons that express dopamine receptors that can be modulated by the D1 or D2 dopamine receptor agonists SKF38393 and (-)-Quinpirole HCl, respectively. Basal immunostaining of hnRNP H was localized primarily to the nucleus. D1 dopamine receptor activation induced an increase in hnRNP H nuclear immunostaining as detected by immunocytochemistry with a C-domain directed antibody containing epitope near the glycine-rich domain but not with an N-domain specific antibody. Although there was no change in hnRNP H protein in the nucleus or cytoplasm, there was a decrease in Hnrnph1 transcript following D1 receptor stimulation. Taken together, these results suggest that D1 receptor activation increases availability of the hnRNP H C-terminal epitope, which could potentially reflect changes in protein-protein interactions. Thus, D1 receptor signaling could represent a key molecular post-synaptic event linking Hnrnph1 polymorphisms to drug-induced behavior.

Determination of Normal Distribution of Distended Colon Volumes to Guide Performance of Colonic Imaging With Fluid Distention.

The purpose was to determine the normal distribution of distended colon volumes as a guide for rectal contrast material administration protocols. All computed tomography colonography studies performed at Emory University Hospital, Atlanta, Georgia, between January 2009 and January 2015, were reviewed retrospectively. In total, 85 subjects were included in the analysis (64% [54 of 85] female and 36% [31 of 85] male). Mean patient age was 65 years (range: 42-86y). Distended colon volumes were determined from colon length and transaxial diameter measurements made using a 3-dimensional workstation. Age, sex, race, height, weight, and body mass index were recorded. The normal distributions of distended colon volumes and lengths were determined. Correlations between colonic volume and colonic length, and demographic variables were assessed. Mean colon volume was 2.1L (range: 0.7-4.4L). Nearly, 17% of patients had a distended colonic volume of >3L. Mean colon length was 197cm (range: 118-285cm). A weak negative correlation was found between age and colonic volume (r = -0.221; P = 0.04). A weak positive correlation was found between body mass index and colonic length (r = 0.368; P = 0.007). Otherwise, no significant correlations were found for distended colonic volume or length and demographic variables. In conclusion, an average of approximately 2L of contrast material may be necessary to achieve full colonic opacification. This volume is larger than previously reported volumes (0.8-1.5L) for rectal contrast material administration protocols.

Clinical characteristics of exacerbations in Parkinson disease.

BACKGROUND: Episodes of subacute worsening of motor function occur commonly in Parkinson disease (PD), but there has been surprisingly little research about the clinical characteristics of these exacerbations in the outpatient setting. METHODS: Retrospective study of an established cohort of 120 outpatients with PD. Primary outcome measures were the frequency, causes, and outcomes of motor exacerbations. Statistical analysis was performed to compare baseline characteristics of subjects with subsequent exacerbations versus without subsequent exacerbations. RESULTS: Over an 18-month period, 43 exacerbations occurred, affecting 30 of 120 subjects (25.0%). Infection was the single most frequent underlying cause, accounting for 11 of 43 (25.6%) exacerbations. Other common etiologies were anxiety (n=8), medication errors (n=6), poor adherence (n=6), medication side effects (n=3), and postoperative decline (n=3). Overall, 35 episodes (81.4%) were attributable to reversible or treatable causes. Most subjects recovered fully, but 10 (33.3%) experienced recurrent episodes, 5 (16.7%) suffered permanent decline, and 1 died. At baseline, subjects with exacerbations had a significantly longer median disease duration (7.8 vs. 5.7 y, P=0.003), lower Mini-Mental State Examination scores (27.0±3.3 vs. 28.6±1.6, P=0.02), higher modified Hoehn and Yahr scores (2.2±0.5 vs. 1.9±0.5, P=0.006), greater dopaminergic medication use (median, 750.0 vs. 395.0 levodopa equivalents; P=0.009), and a greater prevalence of motor complications (55.2% vs. 29.4%, P=0.01) than subjects without exacerbations. CONCLUSIONS: Exacerbations are common in PD, associated with more advanced disease, and usually attributable to treatable secondary causes such as intercurrent infection. Increased recognition of these underlying causes may help to decrease morbidity, reduce health care costs, and optimize quality of care in PD.