Psychosis spectrum illnesses as disorders of prefrontal critical period plasticity.

Emerging research on neuroplasticity processes in psychosis spectrum illnesses-from the synaptic to the macrocircuit levels-fill key gaps in our models of pathophysiology and open up important treatment considerations. In this selective narrative review, we focus on three themes, emphasizing alterations in spike-timing dependent and Hebbian plasticity that occur during adolescence, the critical period for prefrontal system development: (1) Experience-dependent dysplasticity in psychosis emerges from activity decorrelation within neuronal ensembles. (2) Plasticity processes operate bidirectionally: deleterious environmental and experiential inputs shape microcircuits. (3) Dysregulated plasticity processes interact across levels of scale and time and include compensatory mechanisms that have pathogenic importance. We present evidence that-given the centrality of progressive dysplastic changes, especially in prefrontal cortex-pharmacologic or neuromodulatory interventions will need to be supplemented by corrective learning experiences for the brain if we are to help people living with these illnesses to fully thrive.

Nicotinic regulation of local and long-range input balance drives top-down attentional circuit maturation.

Cognitive function depends on frontal cortex development; however, the mechanisms driving this process are poorly understood. Here, we identify that dynamic regulation of the nicotinic cholinergic system is a key driver of attentional circuit maturation associated with top-down frontal neurons projecting to visual cortex. The top-down neurons receive robust cholinergic inputs, but their nicotinic tone decreases following adolescence by increasing expression of a nicotinic brake, Lynx1 Lynx1 shifts a balance between local and long-range inputs onto top-down frontal neurons following adolescence and promotes the establishment of attentional behavior in adulthood. This key maturational process is disrupted in a mouse model of fragile X syndrome but was rescued by a suppression of nicotinic tone through the introduction of Lynx1 in top-down projections. Nicotinic signaling may serve as a target to rebalance local/long-range balance and treat cognitive deficits in neurodevelopmental disorders.

FOLFIRINOX for Advanced Pancreatic Cancer Patients After Nab-Paclitaxel Plus Gemcitabine Failure.

OBJECTIVES: There is no standard chemotherapy for advanced pancreatic cancer (APC) after gemcitabine plus nab-paclitaxel (GP) failure. The aim of this study was to evaluate the efficacy and safety of FOLFIRINOX (5-Fluorouracil, leucovorin, irinotecan, and oxaliplatin) (5-Fluorouracil, leucovorin, irinotecan, and oxaliplatin) (FFX) and modified FFX (mFFX) for APC patients after GP failure. METHODS: We retrospectively evaluated the efficacy and safety of FFX in APC patients who were refractory or intolerant of GP. RESULTS: Between July 2014 and October 2018, 23 patients received FFX after failure of GP. The overall response rate (RR) was 23%, and the disease control rate (DCR) was 68%. The median progression-free survival (PFS) was 5.3 months (95% confidence interval, 2.5-8.9), and the median overall survival (OS) was 12.1 months (95% confidence interval, 4.0-14.2). Twelve patients received FFX, and 11 patients received mFFX. In the FFX group, the RR was 9%, the DCR was 73%, the PFS was 5.3 months, and the OS was 6.9 months. In the mFFX group, the RR was 23%, the DCR was 64%, the PFS was 4.3 months, and the OS was 12.8 months. There was no significant difference between the groups. CONCLUSIONS: FOLFIRINOX has potential activity for patients with APC in whom GP failed.

Takotsubo cardiomyopathy caused by infusion reaction to trastuzumab.

Takotsubo cardiomyopathy (TCM) is also known as stress-induced cardiomyopathy. The occurrence of TCM due to infusion reaction is extremely rare. A 65-year-old man began receiving trastuzumab monotherapy for gastric cancer. However, he developed an infusion reaction after administration. Electrocardiography revealed negative T waves, ST segment elevation, and apical akinesis and hypokinesis of the left ventricle with apical ballooning in the systole and diastole. Furthermore, troponin I and creatinine kinase (CK) levels and CK-myocardial band were elevated. Based on these findings, he was diagnosed with TCM. This is the first report of TCM due to an infusion reaction.

CSF-1 controls cerebellar microglia and is required for motor function and social interaction.

Microglia, the brain resident macrophages, critically shape forebrain neuronal circuits. However, their precise function in the cerebellum is unknown. Here we show that human and mouse cerebellar microglia express a unique molecular program distinct from forebrain microglia. Cerebellar microglial identity was driven by the CSF-1R ligand CSF-1, independently of the alternate CSF-1R ligand, IL-34. Accordingly, CSF-1 depletion from Nestin+ cells led to severe depletion and transcriptional alterations of cerebellar microglia, while microglia in the forebrain remained intact. Strikingly, CSF-1 deficiency and alteration of cerebellar microglia were associated with reduced Purkinje cells, altered neuronal function, and defects in motor learning and social novelty interactions. These findings reveal a novel CSF-1-CSF-1R signaling-mediated mechanism that contributes to motor function and social behavior.

Loss-of-function of neuroplasticity-related genes confers risk for human neurodevelopmental disorders.

High and increasing prevalence of neurodevelopmental disorders place enormous personal and economic burdens on society. Given the growing realization that the roots of neurodevelopmental disorders often lie in early childhood, there is an urgent need to identify childhood risk factors. Neurodevelopment is marked by periods of heightened experience-dependent neuroplasticity wherein neural circuitry is optimized by the environment. If these critical periods are disrupted, development of normal brain function can be permanently altered, leading to neurodevelopmental disorders. Here, we aim to systematically identify human variants in neuroplasticity-related genes that confer risk for neurodevelopmental disorders. Historically, this knowledge has been limited by a lack of techniques to identify genes related to neurodevelopmental plasticity in a high-throughput manner and a lack of methods to systematically identify mutations in these genes that confer risk for neurodevelopmental disorders. Using an integrative genomics approach, we determined loss-of-function (LOF) variants in putative plasticity genes, identified from transcriptional profiles of brain from mice with elevated plasticity, that were associated with neurodevelopmental disorders. From five shared differentially expressed genes found in two mouse models of juvenile-like elevated plasticity (juvenile wild-type or adult Lynx1-/- relative to adult wild-type) that were also genotyped in the Mount Sinai BioMe Biobank we identified multiple associations between LOF genes and increased risk for neurodevelopmental disorders across 10,510 patients linked to the Mount Sinai Electronic Medical Records (EMR), including epilepsy and schizophrenia. This work demonstrates a novel approach to identify neurodevelopmental risk genes and points toward a promising avenue to discover new drug targets to address the unmet therapeutic needs of neurodevelopmental disease.

Nicotinic regulation of experience-dependent plasticity in visual cortex.

While the cholinergic neuromodulatory system and muscarinic acetylcholine receptors (AChRs) have been appreciated as permissive factors for developmental critical period plasticity in visual cortex, it was unknown why plasticity becomes limited after the critical period even in the presence of massive cholinergic projections to visual cortex. In this review we highlighted the recent progresses that started to shed light on the role of the nicotinic cholinergic neuromodulatory signaling on limiting juvenile form of plasticity in the adult brain. We introduce the Lynx family of proteins and Lynx1 as its representative, as endogenous proteins structurally similar to α-bungarotoxin with the ability to bind and modulate nAChRs to effectively regulate functional and structural plasticity. Remarkably, Lynx family members are expressed in distinct subpopulations of GABAergic interneurons, placing them in unique positions to potentially regulate the convergence of GABAergic and nicotinic neuromodulatory systems to regulate plasticity. Continuing studies of the potentially differential roles of Lynx family of proteins may further our understanding of the fundamentals of molecular and cell type-specific mechanisms of plasticity that we may be able to harness through nicotinic cholinergic signaling.

Prolonged Period of Cortical Plasticity upon Redox Dysregulation in Fast-Spiking Interneurons.

BACKGROUND: Oxidative stress and the specific impairment of perisomatic gamma-aminobutyric acid circuits are hallmarks of the schizophrenic brain and its animal models. Proper maturation of these fast-spiking inhibitory interneurons normally defines critical periods of experience-dependent cortical plasticity. METHODS: Here, we linked these processes by genetically inducing a redox dysregulation restricted to such parvalbumin-positive cells and examined the impact on critical period plasticity using the visual system as a model (3-6 mice/group). RESULTS: Oxidative stress was accompanied by a significant loss of perineuronal nets, which normally enwrap mature fast-spiking cells to limit adult plasticity. Accordingly, the neocortex remained plastic even beyond the peak of its natural critical period. These effects were not seen when redox dysregulation was targeted in excitatory principal cells. CONCLUSIONS: A cell-specific regulation of redox state thus balances plasticity and stability of cortical networks. Mistimed developmental trajectories of brain plasticity may underlie, in part, the pathophysiology of mental illness. Such prolonged developmental plasticity may, in turn, offer a therapeutic opportunity for cognitive interventions targeting brain plasticity in schizophrenia.

Perineuronal nets protect fast-spiking interneurons against oxidative stress.

A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks. The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress. Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress. These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults. We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display. Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress. In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets. Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress. The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets. Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.

Pyogenic liver abscess after choledochoduodenostomy for biliary obstruction caused by autoimmune pancreatitis.

A 68-year-old man underwent cholecystectomy and choledochoduodenostomy for biliary obstruction and nephrectomy for a renal tumor. Based on clinical and histopathologic findings, autoimmune pancreatitis (AIP) was diagnosed. The renal tumor was diagnosed as a renal cell cancer. Steroid therapy was started and thereafter pancreatic inflammation improved. Five years after surgery, the patient was readmitted because of pyrexia in a preshock state. A Klebsiella pneumoniae liver abscess complicated by sepsis was diagnosed. The patient recovered with percutaneous abscess drainage and administration of intravenous antibiotics. Liver abscess recurred 1 mo later but was successfully treated with antibiotics. There has been little information on long-term outcomes of patients with AIP treated with surgery. To our knowledge, this is the second case of liver abscess after surgical treatment of AIP.

CNR/Pcdhalpha family in subplate neurons, and developing cortical connectivity.

The cadherin-related neuronal receptor (CNR)/protocadherin (Pcdh) alpha family is one of the diverse protocadherin families identified as a candidate diversified membrane-associated component regulating the formation of neuronal connectivity. However, its expression during neural circuit formation has not been examined in detail. Here, we used a conserved sequence to study the expression of this protein family during the development of neocortical connectivity, by immunohistochemistry and in situ hybridization. The proteins were detected in developing thalamocortical and corticofugal axons, and in subplate neurons, which pioneer these axon tracts. The expression in subplate neurons was confirmed by birth-date labeling with BrdU, and by examination in homozygous reeler mice. This pattern of CNR/Pcdhalpha expression suggests its involvement in the development of neocortical connectivity.

Interaction with protocadherin-gamma regulates the cell surface expression of protocadherin-alpha.

The protocadherin-alpha (CNR/Pcdhalpha) and protocadherin-gamma (Pcdhgamma) proteins, members of the cadherin superfamily, are putative cell recognition/adhesion molecules in the brain. Overexpressed cadherins are generally expressed on the cell surface and elicit cell adhesion activity in several cell lines, although hardly any overexpressed CNR/Pcdhalpha proteins are expressed on the cell surface, except on HEK293T cells, which show low expression. We analyzed the expression of CNR/Pcdhalpha and Pcdhgamma in HEK293T cells and found that they formed a protein complex and that Pcdhgamma enhanced the surface expression of CNR/Pcdhalpha. This enhanced surface expression was confirmed by flow cytometry analysis and by marking cell surface proteins with biotin. The enhancement was observed using different combinations of CNR/Pcdhalpha and Pcdhgamma proteins. The surface expression activity was enhanced by the extracellular domains of the proteins, which could bind each other. Their cytoplasmic domains also had binding activity and influenced their localization. Their protein-protein interaction was also detected in extracts of mouse brain and two neuroblastoma cell lines. Thus, interactions between CNR/Pcdhalpha and Pcdhgamma regulate their surface expression and contribute to the combinatorial diversity of cell recognition proteins in the brain.