Neural precursor cells tune striatal connectivity through the release of IGFBPL1.

The adult brain retains over life endogenous neural stem/precursor cells (eNPCs) within the subventricular zone (SVZ). Whether or not these cells exert physiological functions is still unclear. In the present work, we provide evidence that SVZ-eNPCs tune structural, electrophysiological, and behavioural aspects of striatal function via secretion of insulin-like growth factor binding protein-like 1 (IGFBPL1). In mice, selective ablation of SVZ-eNPCs or selective abrogation of IGFBPL1 determined an impairment of striatal medium spiny neuron morphology, a higher failure rate in GABAergic transmission mediated by fast-spiking interneurons, and striatum-related behavioural dysfunctions. We also found IGFBPL1 expression in the human SVZ, foetal and induced-pluripotent stem cell-derived NPCs. Finally, we found a significant correlation between SVZ damage, reduction of striatum volume, and impairment of information processing speed in neurological patients. Our results highlight the physiological role of adult SVZ-eNPCs in supporting cognitive functions by regulating striatal neuronal activity.

Scn1a gene reactivation after symptom onset rescues pathological phenotypes in a mouse model of Dravet syndrome.

Dravet syndrome is a severe epileptic encephalopathy caused primarily by haploinsufficiency of the SCN1A gene. Repetitive seizures can lead to endurable and untreatable neurological deficits. Whether this severe pathology is reversible after symptom onset remains unknown. To address this question, we generated a Scn1a conditional knock-in mouse model (Scn1a Stop/+) in which Scn1a expression can be re-activated on-demand during the mouse lifetime. Scn1a gene disruption leads to the development of seizures, often associated with sudden unexpected death in epilepsy (SUDEP) and behavioral alterations including hyperactivity, social interaction deficits and cognitive impairment starting from the second/third week of age. However, we showed that Scn1a gene re-activation when symptoms were already manifested (P30) led to a complete rescue of both spontaneous and thermic inducible seizures, marked amelioration of behavioral abnormalities and normalization of hippocampal fast-spiking interneuron firing. We also identified dramatic gene expression alterations, including those associated with astrogliosis in Dravet syndrome mice, that, accordingly, were rescued by Scn1a gene expression normalization at P30. Interestingly, regaining of Nav1.1 physiological level rescued seizures also in adult Dravet syndrome mice (P90) after months of repetitive attacks. Overall, these findings represent a solid proof-of-concept highlighting that disease phenotype reversibility can be achieved when Scn1a gene activity is efficiently reconstituted in brain cells.

Administration of aerosolized SARS-CoV-2 to K18-hACE2 mice uncouples respiratory infection from fatal neuroinvasion.

The development of a tractable small animal model faithfully reproducing human coronavirus disease 2019 pathogenesis would arguably meet a pressing need in biomedical research. Thus far, most investigators have used transgenic mice expressing the human ACE2 in epithelial cells (K18-hACE2 transgenic mice) that are intranasally instilled with a liquid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suspension under deep anesthesia. Unfortunately, this experimental approach results in disproportionate high central nervous system infection leading to fatal encephalitis, which is rarely observed in humans and severely limits this model's usefulness. Here, we describe the use of an inhalation tower system that allows exposure of unanesthetized mice to aerosolized virus under controlled conditions. Aerosol exposure of K18-hACE2 transgenic mice to SARS-CoV-2 resulted in robust viral replication in the respiratory tract, anosmia, and airway obstruction but did not lead to fatal viral neuroinvasion. When compared with intranasal inoculation, aerosol infection resulted in a more pronounced lung pathology including increased immune infiltration, fibrin deposition, and a transcriptional signature comparable to that observed in SARS-CoV-2­infected patients. This model may prove useful for studies of viral transmission, disease pathogenesis (including long-term consequences of SARS-CoV-2 infection), and therapeutic interventions.

Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients.

Adenosine Deaminase (ADA) deficiency is an autosomal recessive variant of severe combined immunodeficiency (SCID) caused by systemic accumulation of ADA substrates. Neurological and behavioral abnormalities observed in ADA-SCID patients surviving after stem cell transplantation or gene therapy represent an unresolved enigma in the field. We found significant neurological and cognitive alterations in untreated ADA-SCID patients as well as in two groups of patients after short- and long-term enzyme replacement therapy with PEG-ADA. These included motor dysfunction, EEG alterations, sensorineural hypoacusia, white matter and ventricular alterations in MRI as well as a low mental development index or IQ. Ada-deficient mice were significantly less active and showed anxiety-like behavior. Molecular and metabolic analyses showed that this phenotype coincides with metabolic alterations and aberrant adenosine receptor signaling. PEG-ADA treatment corrected metabolic adenosine-based alterations, but not cellular and signaling defects, indicating an intrinsic nature of the neurological and behavioral phenotype in ADA deficiency.

Niacin-mediated Tace activation ameliorates CMT neuropathies with focal hypermyelination.

Charcot-Marie-Tooth (CMT) neuropathies are highly heterogeneous disorders caused by mutations in more than 70 genes, with no available treatment. Thus, it is difficult to envisage a single suitable treatment for all pathogenetic mechanisms. Axonal Neuregulin 1 (Nrg1) type III drives Schwann cell myelination and determines myelin thickness by ErbB2/B3-PI3K-Akt signaling pathway activation. Nrg1 type III is inhibited by the α-secretase Tace, which negatively regulates PNS myelination. We hypothesized that modulation of Nrg1 levels and/or secretase activity may constitute a unifying treatment strategy for CMT neuropathies with focal hypermyelination as it could restore normal levels of myelination. Here we show that in vivo delivery of Niaspan, a FDA-approved drug known to enhance TACE activity, efficiently rescues myelination in the Mtmr2-/- mouse, a model of CMT4B1 with myelin outfoldings, and in the Pmp22+/- mouse, which reproduces HNPP (hereditary neuropathy with liability to pressure palsies) with tomacula. Importantly, we also found that Niaspan reduces hypermyelination of Vim (vimentin)-/- mice, characterized by increased Nrg1 type III and Akt activation, thus corroborating the hypothesis that Niaspan treatment downregulates Nrg1 type III signaling.

Increased neuroplasticity and hippocampal microglia activation in a mice model of rapid antidepressant treatment.

The search for biomarkers of antidepressant effects focused on pathways regulating synaptic plasticity, and on activated inflammatory markers. Repeated Sleep Deprivation (SD) provides a model treatment to reverse-translate antidepressant effects from in vivo clinical psychiatry to model organisms. We studied the effects of repeated SD alone (ASD) or combined with exercise on a slow spinning wheel (SSW), in 116 C57BL/6J male mice divided in three groups (ASD, SSW, untreated). Forced Swimming Test (FST) was used to detect antidepressant-like effects. Unbiased evaluation of the transcriptional responses were obtained in the hippocampus by Illumina Bead Chip Array system, then confirmed with real time PCR. Spine densities in granular neurons of the dentate gyrus (DG) were assayed by standard Golgi staining. Activation of Microglial/Macrophages cells was evaluated by immunufluorescence analysis for Iba1. Rates of cell proliferation was estimated pulsing mice with the S-phase tracer 5-Iodo-2'-deoxyuridine (IdU). All SD procedures caused a decreasing of floating time at FST, and increased expression of the immediate early gene Arc/Arg3.1. In addition, SSW also increased expression of the Microglia/Macrophages genes Iba-1 and chemokine receptors Cx3cR1 and CxcR4, of the canonical Wnt signaling gene Wnt7a, and of dendritic spines in CA4 neurons of the DG. SSW up-regulated both the number of Iba1+ cells and rates of cell proliferation in the subgranular region of the DG. The antidepressant-like effects of SD dissociated both, from hippocampal neuroplasticity in the DG (not occurring after ASD), and from microglial activation (not preventing behavioral response when occurring). The increase in dendritic spine density in the DG after SD and exercise was associated with an up-regulation of Wnt 7a, and with activation of the innate immune system of the brain. Increased Arc/Arg3.1 suggests however increased neuroplasticity, which could be common to all fast-acting antidepressants, and possibly occurring in other brain areas.

2-Deoxy-d-Glucose Ameliorates PKD Progression.

Autosomal dominant polycystic kidney disease (ADPKD) is an important cause of ESRD for which there exists no approved therapy in the United States. Defective glucose metabolism has been identified as a feature of ADPKD, and inhibition of glycolysis using glucose analogs ameliorates aggressive PKD in preclinical models. Here, we investigated the effects of chronic treatment with low doses of the glucose analog 2-deoxy-d-glucose (2DG) on ADPKD progression in orthologous and slowly progressive murine models created by inducible inactivation of the Pkd1 gene postnatally. As previously reported, early inactivation (postnatal days 11 and 12) of Pkd1 resulted in PKD developing within weeks, whereas late inactivation (postnatal days 25-28) resulted in PKD developing in months. Irrespective of the timing of Pkd1 gene inactivation, cystic kidneys showed enhanced uptake of (13)C-glucose and conversion to (13)C-lactate. Administration of 2DG restored normal renal levels of the phosphorylated forms of AMP-activated protein kinase and its target acetyl-CoA carboxylase. Furthermore, 2DG greatly retarded disease progression in both model systems, reducing the increase in total kidney volume and cystic index and markedly reducing CD45-positive cell infiltration. Notably, chronic administration of low doses (100 mg/kg 5 days per week) of 2DG did not result in any obvious sign of toxicity as assessed by analysis of brain and heart histology as well as behavioral tests. Our data provide proof of principle support for the use of 2DG as a therapeutic strategy in ADPKD.