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Fragile X is the most common monogenic disorder associated with intellectual disability (ID) and autism spectrum disorders (ASD). Additionally, many patients are afflicted with executive dysfunction, ADHD, seizure disorder and sleep disturbances. Fragile X is caused by loss of FMRP expression, which is encoded by the FMR1 gene. Both the fly and mouse models of fragile X are also based on having no functional protein expression of their respective FMR1 homologs. The fly model displays well defined cognitive impairments and structural brain defects and the mouse model, although having subtle behavioral defects, has robust electrophysiological phenotypes and provides a tool to do extensive biochemical analysis of select brain regions. Decreased cAMP signaling has been observed in samples from the fly and mouse models of fragile X as well as in samples derived from human patients. Indeed, we have previously demonstrated that strategies that increase cAMP signaling can rescue short term memory in the fly model and restore DHPG induced mGluR mediated long term depression (LTD) in the hippocampus to proper levels in the mouse model (McBride et al., 2005; Choi et al., 2011, 2015). Here, we demonstrate that the same three strategies used previously with the potential to be used clinically, lithium treatment, PDE-4 inhibitor treatment or mGluR antagonist treatment can rescue long term memory in the fly model and alter the cAMP signaling pathway in the hippocampus of the mouse model. [ABSTRACT FROM AUTHOR]

Dopaminergic and glutamatergic systems are critical components responsible for prefrontal signal-to-noise tuning in working memory. Recent functional MRI (fMRI) studies of genetic variation in these systems in catechol-O-methyltransferase (COMT) and in metabotropic glutamate receptor mgluR3 (GRM3). respectively, suggest that these genes influence prefrontal physiological signal- to-noise in humans. Here, using fMRI, we extend these individual gene findings to examine the combined effects of COMT and GRM3 on dissociable components of the frontoparietal working memory network. We observed an apparent epistatic interaction of these two genes on the engagement of prefrontal cortex during working memory. Specifically, the GRM3 genotype putatively associated with suboptimal glutamatergic signaling was significantly associated with inefficient prefrontal engagement and altered prefrontal- parietal coupling on the background of COMT Val-homozygous genotype. Conversely. COMT Met-homozygous background mediated against the effect of GRM3 genotype. These findings extend putative brain dopaminergic and glutamatergic relationships indexed by COMT and GRM3 to a systems-level interaction in human cortical circuits implicated in working memory dysfunction such as in schizophrenia. [ABSTRACT FROM AUTHOR]

Regulator of G-protein signaling 4 (RGS4) modulates postsynaptic signal transduction by affecting the kinetics of Gα-GTP binding. Linkage, association, and postmortem studies have implicated the gene encoding RGS4 (RGS4) as a schizophrenia susceptibility factor. Using a multimodal neuroimaging approach, we demonstrate that genetic variation in RGS4 is associated with functional activation and connectivity during working memory in the absence of overt behavioral differences, with regional gray and white matter volume and with gray matter structural connectivity in healthy human subjects. Specifically, variation at one RGS4 single nucleotide polymorphism that has been associated previously with psychosis (rs951436) impacts frontoparietal and frontotemporal blood oxygenation level-dependent response and network coupling during working memory and results in regionally specific reductions in gray and white matter structural volume in individuals carrying the A allele. These findings suggest mechanisms in brain for the association of RGS4 with risk for psychiatric illness. [ABSTRACT FROM AUTHOR]

Objectivo: Se ha sugerido que el procesamiento cognitivo de orden superior requerido por la carga creciente de la memoria de trabajo en las personas sanas emplea jerárquicamente más recursos de la región dorsal prefrontal que de la ventral. Dado que en la esquizofrenia se encuentra afectado el rendimiento de la memoria de trabajo, especialmente con cargas de ejecución más elevadas, los autores investigaron de qué manera podría alterarse esta organización funcional prefrontal en caso de enfermedad, con independencia de los déficit de rendimiento. Método: Mediante resonancia magnética funcional (FMf) y una prueba de memoria de trabajo bajo el paradigma N-back, los autores estudiaron a 15 pacientes con esquizofrenia y a 26 individuos sanos de control. Se analizaron los subgrupos formados sobre la base de la precisión mediana del rendimiento en 2-back; 8 pacientes con esquizofrenia y 14 individuos de control tuvieron un rendimiento alto, y 7 pacientes y 12 individuos de control, un rendimiento bajo. Resultados: A diferencia de los individuos de control con rendimiento bajo, los individuos con rendimiento alto respondieron a la carga creciente de la memoria de ejecución con una activación de la corteza prefrontal dorsal desproporcionadamente mayor, que también pronosticó la precisión de la ejecución, pero no sucedió la precisón de la ejecución, pero no sucedió lo mismo con la corteza prefrontal ventral. En los grupos de pacientes con rendimiento alto y bajo, comparados con el grupo de individuos correspondiente, la carga creciente de la memoria de trabajo produjo un aumenteo desproporcionado de la activación de la corteza prefrontal ventral, pero no de la prefrontal dorsa, que también se relacionó con la precisión. La conectividad funcional entre la corteza prefrontal ventral y la corteza parietal posterior fue relativamente mayor en los pacientes, mientras que los individuos de control mostraron una mayor conectividad funcional entre la corteza prefrontal dorsal y corteza parietal posterior. Conclusiones: En la esquizofrenia podría estar afectada la organización jerárquica de la corteza prefrontal, lo cual provocaría, por un lado, una pérdida de la especialización funcional y de la integreción de la corteza prefrontal dorsal y, por otro, la activacón compensadora de la corteza prefrontal ventral, que en última instancia afectaría a la memoria de trabajo y a la cognición ejecutiva. [ABSTRACT FROM AUTHOR]

Objective: It has been suggested that in healthy persons higher-order cognitive processing engaged by incremental working memory load hierarchically employs more dorsal than ventral prefrontal resources in healthy individuals. Given that working memory performance is impaired in schizophrenia, especially at higher executive loads, the authors investigated how this prefrontal functional organization might be altered in disease, independent of performance deficits, Method: Using N-back working memory functional magnetic resonance imaging (fMRI) data, the authors studied 15 patients with schizophrenia and 26 healthy comparison subjects. Subgroups based on median performance accuracy at 2-back were analyzed; high performers included eight schizophrenia patients and 14 comparison subjects, and low performers included seven patients and 12 comparison subjects. Results: High-performing but not low-performing comparison subjects responded to incremental working memory executive load with disproportionately greater dorsal but not ventral prefrontal cortex activation, which also predicted performance accuracy. In the high- and low-performing patient groups, incremental working memory load caused a disproportionate increase in ventral but not dorsal prefrontal cortex activation relative to the respective comparison group, which also correlated with accuracy. Functional connectivity between the ventral prefrontal cortex and posterior parietal cortex was relatively greater in patients, whereas comparison subjects had greater functional connectivity between the dorsal prefrontal cortex and posterior parietal cortex. Conclusions: The hierarchical organization of the prefrontal cortex may be compromised in schizophrenia, resulting in loss of functional specialization and integration at the dorsal prefrontal cortex and in compensatory activation from the ventral prefrontal cortex, which may ultimately affect working memory and executive cognition. [ABSTRACT FROM AUTHOR]