Impact of feeding age on cognitive impairment in mice with Disrupted-In-Schizophrenia 1 (Disc1) mutation under a high sucrose diet.

A combination of genetic predisposition and environmental factors contributes to the development of psychiatric disorders such as schizophrenia, bipolar disorder and major depressive disorder. Previous studies using mouse models suggested that prolonged high sucrose intake during puberty can serve as an environmental risk factor for the onset of psychiatric disorders. However, the impact of both the duration and timing of high sucrose consumption during different developmental stages on pathogenesis remains poorly defined.

Ribosomal dysregulation: A conserved pathophysiological mechanism in human depression and mouse chronic stress.

The underlying biological mechanisms that contribute to the heterogeneity of major depressive disorder (MDD) presentation remain poorly understood, highlighting the need for a conceptual framework that can explain this variability and bridge the gap between animal models and clinical endpoints. Here, we hypothesize that comparative analysis of molecular data from different experimental systems of chronic stress, and MDD has the potential to provide insight into these mechanisms and address this gap. Thus, we compared transcriptomic profiles of brain tissue from postmortem MDD subjects and from mice exposed to chronic variable stress (CVS) to identify orthologous genes.

BS3 Chemical Crosslinking Assay: Evaluating the Effect of Chronic Stress on Cell Surface GABAA Receptor Presentation in the Rodent Brain.

Anxiety is a state of emotion that variably affects animal behaviors, including cognitive functions. Behavioral signs of anxiety are observed across the animal kingdom and can be recognized as either adaptive or maladaptive responses to a wide range of stress modalities. Rodents provide a proven experimental model for translational studies addressing the integrative mechanisms of anxiety at the molecular, cellular, and circuit levels.

Regulation of sensorimotor gating via Disc1/Huntingtin-mediated Bdnf transport in the cortico-striatal circuit.

Sensorimotor information processing underlies normal cognitive and behavioral traits and has classically been evaluated through prepulse inhibition (PPI) of a startle reflex. PPI is a behavioral dimension deregulated in several neurological and psychiatric disorders, yet the mechanisms underlying the cross-diagnostic nature of PPI deficits across these conditions remain to be understood. To identify circuitry mechanisms for PPI, we performed circuitry recording over the prefrontal cortex and striatum, two brain regions previously implicated in PPI, using wild-type (WT) mice compared to Disc1-locus-impairment (LI) mice, a model representing neuropsychiatric conditions.

Molecular origin of somatostatin-positive neuron vulnerability.

Reduced somatostatin (SST) and dysfunction of SST-positive (SST) neurons are hallmarks of neurological disorders and associated with mood disturbances, but the molecular origin of SST neuron vulnerability is unknown. Using chronic psychosocial stress as a paradigm to induce elevated behavioral emotionality in rodents, we report a selective vulnerability of SST neurons through exacerbated unfolded protein response (UPR) of the endoplasmic reticulum (ER), or ER stress, in the prefrontal cortex. We next show that genetically suppressing ER stress in SST neurons, but not in pyramidal neurons, normalized behavioral emotionality induced by psychosocial stress.

High-sucrose diets contribute to brain angiopathy with impaired glucose uptake and psychosis-related higher brain dysfunctions in mice.

Metabolic dysfunction is thought to contribute to the severity of psychiatric disorders; however, it has been unclear whether current high–simple sugar diets contribute to pathogenesis of these diseases. Here, we demonstrate that a high-sucrose diet during adolescence induces psychosis-related behavioral endophenotypes, including hyperactivity, poor working memory, impaired sensory gating, and disrupted interneuron function in mice deficient for glyoxalase-1 (GLO1), an enzyme involved in detoxification of sucrose metabolites. Furthermore, the high-sucrose diet induced microcapillary impairments and reduced brain glucose uptake in brains of -deficient mice.

Molecular characterization of depression trait and state.

Major depressive disorder (MDD) is a brain disorder often characterized by recurrent episode and remission phases. The molecular correlates of MDD have been investigated in case-control comparisons, but the biological alterations associated with illness trait (regardless of clinical phase) or current state (symptomatic and remitted phases) remain largely unknown, limiting targeted drug discovery. To characterize MDD trait- and state-dependent changes, in single or recurrent depressive episode or remission, we generated transcriptomic profiles of subgenual anterior cingulate cortex of postmortem subjects in first MDD episode (n = 20), in remission after a single episode (n = 15), in recurrent episode (n = 20), in remission after recurring episodes (n = 15) and control subject (n = 20).

Autophagy in neuronal physiology and disease.

Neural circuit functions critically depend on homeostatic regulation and quality control of neuronal proteins and organelles. Emerging evidence shows that autophagy, cellular clearance machinery, selectively degrades or controls homeostasis of both pre- and post-synaptic components (e.g.

BDNF controls GABAR trafficking and related cognitive processes via autophagic regulation of p62.

Reduced brain-derived neurotrophic factor (BDNF) and gamma-aminobutyric acid (GABA) neurotransmission co-occur in brain conditions (depression, schizophrenia and age-related disorders) and are associated with symptomatology. Rodent studies show they are causally linked, suggesting the presence of biological pathways mediating this link. Here we first show that reduced BDNF and GABA also co-occur with attenuated autophagy in human depression.

Reversal of Age-Related Neuronal Atrophy by α5-GABAA Receptor Positive Allosteric Modulation.

Aging is associated with reduced brain volume, altered neural activity, and neuronal atrophy in cortical-like structures, comprising the frontal cortex and hippocampus, together contributing to cognitive impairments. Therapeutic efforts aimed at reversing these deficits have focused on excitatory or neurotrophic mechanisms, although recent findings show that reduced dendritic inhibition mediated by α5-subunit containing GABA-A receptors (α5-GABAA-Rs) occurs during aging and contributes to cognitive impairment. Here, we aimed to confirm the beneficial effect on working memory of augmenting α5-GABAA-R activity in old mice and tested its potential at reversing age-related neuronal atrophy.

Neuronal Autophagy in Synaptic Functions and Psychiatric Disorders.

Homeostatic maintenance of physiological functions is fundamental to organismal well-being. Disruption or imbalance in homeostasis results in functional disturbances at molecular, cellular, and tissue levels, leading to manifestation as physical and mental illnesses. Homeostatic imbalance is caused by a range of pathophysiological mechanisms, including disrupted reduction-oxidation reactions, inflammatory responses, metabolic disturbances, or failure in quality control of cellular proteins and organelles.

The transcriptome landscape associated with Disrupted-in-Schizophrenia-1 locus impairment in early development and adulthood.

DISC1 was originally expected to be a genetic risk factor for schizophrenia, but the genome wide association studies have not supported this idea. In contrast, neurobiological studies of DISC1 in cell and animal models have demonstrated that direct perturbation of DISC1 protein elicits neurobiological and behavioral abnormalities relevant to a wide range of psychiatric conditions, in particular psychosis. Thus, the utility of DISC1 as a biological lead for psychosis research is clear.

A mouse model of 22q11.2 deletions: Molecular and behavioral signatures of Parkinson's disease and schizophrenia.

Individuals with chromosome 22q11.2 deletions are at increased risk of developing psychiatric conditions, most notably, schizophrenia (SZ). Recently, clinical studies have also implicated these recurrent 22q11.

Ulk2 controls cortical excitatory-inhibitory balance via autophagic regulation of p62 and GABAA receptor trafficking in pyramidal neurons.

Autophagy plays an essential role in intracellular degradation and maintenance of cellular homeostasis in all cells, including neurons. Although a recent study reported a copy number variation of Ulk2, a gene essential for initiating autophagy, associated with a case of schizophrenia (SZ), it remains to be studied whether Ulk2 dysfunction could underlie the pathophysiology of the disease. Here we show that Ulk2 heterozygous (Ulk2+/-) mice have upregulated expression of sequestosome-1/p62, an autophagy-associated stress response protein, predominantly in pyramidal neurons of the prefrontal cortex (PFC), and exhibit behavioral deficits associated with the PFC functions, including attenuated sensorimotor gating and impaired cognition.

Methylphenidate and Guanfacine Ameliorate ADHD-Like Phenotypes in -Deficient Mice.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that, while prevalent, has a stagnant track record for advances in treatment. The limited availability of animal models with appropriate face and predictive validities has hampered progress in developing novel neurobiological hypotheses and testing new therapeutic options for this condition. Here, we report that mice deficient in , a gene specifically expressed in the nervous system with documented functions in neurodevelopment, show hyperactivity and impulsivity phenotypes, which are ameliorated by administering methylphenidate (MPH) or guanfacine (GFC), two pharmacological agents used for ADHD treatment.

[Neural circuitry and brain functions.].

To understand the fundamentals of brain functions and our mind, it is essential to elucidate working principles of neural circuit activity orchestrated by the activities of single neurons. To achieve this goal, several big projects are ongoing worldwide to decode brain connectomes at micro- through macro-scales, aiming at obtaining a whole picture of neural connectivity ranging from single neurons, group of neurons, functional brain areas, and connections between the areas, and to understand the structure and functions of our brain. We will briefly overview these ongoing efforts and discuss issues that need to be solved as we move forward.

[C]()-Rolipram positron emission tomography detects DISC1 inhibition of phosphodiesterase type 4 in live locus-impaired mice.

Although still a matter of controversy, disrupted in schizophrenia protein 1 (DISC1) was suggested as a potential inhibitor of phosphodiesterase 4 (PDE4). We used locus impairment (LI) mice to investigate the interaction between PDE4 and DISC 1 and . [C]()-Rolipram binding was measured by PET in LI ( = 11) and C57BL/6 wild-type (WT,  = 9) mice.

Role of DISC1 in Neuronal Trafficking and its Implication in Neuropsychiatric Manifestation and Neurotherapeutics.

Disrupted-in-schizophrenia 1 (DISC1) was initially identified as a gene disrupted by a translocation mutation co-segregating with a variety of psychotic and mood disorders in a Scottish pedigree. In agreement with this original finding, mouse models that perturb Disc1 display deficits of behaviors in specific dimensions, such as cognition and emotion, but not a motor dimension. Although DISC1 is not a risk gene for sporadic cases of specific psychiatric disorders defined by categorical diagnostic criteria (e.

Ulk1 protects against ethanol-induced neuronal stress and cognition-related behavioral deficits.

Alcoholism is a psychiatric condition that develops through neuroadaptations in response to neuronal stresses caused by chronic ethanol intake. Neurons can adapt to ethanol-induced metabolic changes by activating cellular protective mechanisms, including autophagy. Here we show that expression of Ulk1, a gene critical to the regulation of autophagy, was affected in the prefrontal cortex (PFC) of mice following chronic intermittent ethanol (CIE) exposure.

Interneuronal DISC1 regulates NRG1-ErbB4 signalling and excitatory-inhibitory synapse formation in the mature cortex.

Neuregulin-1 (NRG1) and its receptor ErbB4 influence several processes of neurodevelopment, but the mechanisms regulating this signalling in the mature brain are not well known. DISC1 is a multifunctional scaffold protein that mediates many cellular processes. Here we present a functional relationship between DISC1 and NRG1-ErbB4 signalling in mature cortical interneurons.

Converging models of schizophrenia--Network alterations of prefrontal cortex underlying cognitive impairments.

The prefrontal cortex (PFC) and its connections with other brain areas are crucial for cognitive function. Cognitive impairments are one of the core symptoms associated with schizophrenia, and manifest even before the onset of the disorder. Altered neural networks involving PFC contribute to cognitive impairments in schizophrenia.

DISC1 regulates synaptic vesicle transport via a lithium-sensitive pathway.

Disrupted-in-Schizophrenia 1 (DISC1) is a susceptibility gene for major mental illnesses, including bipolar disorder and schizophrenia. Although the roles of DISC1 in nervous system development and functions are increasingly recognized, pathophysiological mechanisms underlying a range of neuropsychiatric symptoms caused by DISC1 mutations remain unclear. Here we show that DISC1 enhances synaptic vesicle transport along microtubules.

Unc-51/ATG1 controls axonal and dendritic development via kinesin-mediated vesicle transport in the Drosophila brain.

Background: Members of the evolutionary conserved Ser/Thr kinase Unc-51 family are key regulatory proteins that control neural development in both vertebrates and invertebrates. Previous studies have suggested diverse functions for the Unc-51 protein, including axonal elongation, growth cone guidance, and synaptic vesicle transport.

Methodology/principal Findings: In this work, we have investigated the functional significance of Unc-51-mediated vesicle transport in the development of complex brain structures in Drosophila.

Unc-51 controls active zone density and protein composition by downregulating ERK signaling.

Efficient synaptic transmission requires the apposition of neurotransmitter release sites opposite clusters of postsynaptic neurotransmitter receptors. Transmitter is released at active zones, which are composed of a large complex of proteins necessary for synaptic development and function. Many active zone proteins have been identified, but little is known of the mechanisms that ensure that each active zone receives the proper complement of proteins.