Daniel R. Weinberger

Modeling a Genetic Risk for Schizophrenia in iPSCs and Mice Reveals Neural Stem Cell Deficits Associated with Adherens Junctions and Polarity

Defects in brain development are believed to contribute toward the onset of neuropsychiatric disorders, but identifying specific underlying mechanisms has proven difficult. Here, we took a multifaceted approach to investigate why 15q11.2 copy number variants are prominent risk factors for schizophrenia and autism. First, we show that human iPSC-derived neural progenitors carrying 15q11.2 microdeletion exhibit deficits in adherens junctions and apical polarity. This results from haploinsufficiency of CYFIP1, a gene within 15q11.2 that encodes a subunit of thexa0WAVE complex, which regulates cytoskeletal dynamics. In developing mouse cortex, deficiency in CYFIP1 and WAVE signaling similarly affects radial glial cells, leading to their ectopic localization outside of the ventricular zone. Finally, targeted human genetic association analyses revealed an epistatic interaction between CYFIP1 and WAVE signaling mediator ACTR2 and risk for schizophrenia. Our findings provide insight into how CYFIP1 regulates neural stem cell function and may contribute to the susceptibility of neuropsychiatric disorders.

DSM-5: a collection of psychiatrist views on the changes, controversies, and future directions

The recent release of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) by the American Psychiatric Association has led to much debate. For this forum article, we asked BMC Medicine Editorial Board members who are experts in the field of psychiatry to discuss their personal views on how the changes in DSM-5 might affect clinical practice in their specific areas of psychiatric medicine. This article discusses the influence the DSM-5 may have on the diagnosis and treatment of autism, trauma-related and stressor-related disorders, obsessive-compulsive and related disorders, mood disorders (including major depression and bipolar disorders), and schizophrenia spectrum disorders.

Dissociating Bottom-Up and Top-Down Mechanisms in the Cortico-Limbic System during Emotion Processing

The cortico-limbic system is critically involved in emotional responses and resulting adaptive behaviors. Within this circuit, complementary regions are believed to be involved in either the appraisal or the regulation of affective state. However, the respective contribution of these bottom-up and top-down mechanisms during emotion processing remains to be clarified. We used a new functional magnetic resonance imaging (fMRI) paradigm varying 3 parameters: emotional valence, emotional congruency, and allocation of attention, to distinguish the functional variation in activity and connectivity between amygdala, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC). Bottom-up appraisal of negative compared with positive stimuli led to a greater amygdala response and stronger functional interaction between amygdala and both dorsal ACC and DLPFC. Top-down resolution of emotional conflict was associated with increased activity within ACC and higher functional connectivity between this structure, and both the amygdala and DLPFC. Finally, increased top-down attentional control caused greater engagement of the DLPFC, accompanied by increased connectivity between DLPFC and dorsal ACC. This novel task provides an efficient tool for exploring bottom-up and top-down processes underlying emotion and may be particularly helpful for investigating the neurofunctional underpinnings of psychiatric disorders.

Potential role of the combination of galantamine and memantine to improve cognition in schizophrenia

The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and Schizophrenia projects were designed to facilitate the development of new drugs for the treatment of cognitive impairments in people with schizophrenia. The MATRICS project identified three drug mechanisms of particular interest: dopaminergic, cholinergic, and glutamatergic. As a group, while people with schizophrenia have moderate cognitive impairment, it is the best predictor of long-term outcome. Unfortunately, there are no approved medications for cognitive impairment in this population. Hence, the development of new pharmacological approaches is critical for reducing illness-related disability. The combination of an acetylcholinesterase inhibitor (AChEI) and memantine is more effective than either medication alone to improve cognition in Alzheimers dementia. Galantamine is not only an AChEI, but also a positive allosteric modulator of the α4β2 and α7 nicotinic receptors. Hypofunction of N-methyl-d-aspartate (NMDA) receptors has been implicated in the pathophysiology of cognitive symptoms in schizophrenia and hence memantine may positively impact cognition. Memantine decreases the tonic NMDA current and galantamine enhances the action potential mediated by a postsynaptic NMDA current. This results in an increased signal transmission; therefore, a greater signal-to-noise ratio occurs with the combination than memantine alone. Galantamine improves the α-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA)-mediated signaling which could be neuroprotective and may improve memory coding. The combination of galantamine and memantine may be particularly effective in schizophrenia in order to increase the selective cognition enhancement produced by either medication alone. In the future, multitarget-directed ligands may play a role in the treatment of complex diseases like schizophrenia.

Effect of trait anxiety on prefrontal control mechanisms during emotional conflict.

Converging evidence points to a link between anxiety proneness and altered emotional functioning, including threat‐related biases in selective attention and higher susceptibility to emotionally ambiguous stimuli. However, during these complex emotional situations, it remains unclear how trait anxiety affects the engagement of the prefrontal emotional control system and particularly the anterior cingulate cortex (ACC), a core region at the intersection of the limbic and prefrontal systems. Using an emotional conflict task and functional magnetic resonance imaging (fMRI), we investigated in healthy subjects the relations between trait anxiety and both regional activity and functional connectivity (psychophysiological interaction) of the ACC. Higher levels of anxiety were associated with stronger task‐related activation in ACC but with reduced functional connectivity between ACC and lateral prefrontal cortex (LPFC). These results support the hypothesis that when one is faced with emotionally incompatible information, anxiety leads to inefficient high‐order control, characterized by insufficient ACC‐LPFC functional coupling and increases, possibly compensatory, in activation of ACC. Our findings provide a deeper understanding of the pathophysiology of the neural circuitry underlying anxiety and may offer potential treatment markers for anxiety disorders. Hum Brain Mapp 36:2207–2214, 2015.

GAD2 alternative transcripts in the human prefrontal cortex, and in schizophrenia and affective disorders

Genetic variation and early adverse environmental events work together to increase risk for schizophrenia. γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in adult mammalian brain, plays a major role in normal brain development, and has been strongly implicated in the pathobiology of schizophrenia. GABA synthesis is controlled by two glutamic acid decarboxylase (GAD) genes, GAD1 and GAD2, both of which produce a number of alternative transcripts. Genetic variants in the GAD1 gene are associated with increased risk for schizophrenia, and reduced expression of its major transcript in the human dorsolateral prefrontal cortex (DLPFC). No consistent changes in GAD2 expression have been found in brains from patients with schizophrenia. In this work, with the use of RNA sequencing and PCR technologies, we confirmed and tracked the expression of an alternative truncated transcript of GAD2 (ENST00000428517) in human control DLPFC homogenates across lifespan besides the well-known full length transcript of GAD2. In addition, using quantitative RT-PCR, expression of GAD2 full length and truncated transcripts were measured in the DLPFC of patients with schizophrenia, bipolar disorder and major depression. The expression of GAD2 full length transcript is decreased in the DLPFC of schizophrenia and bipolar disorder patients, while GAD2 truncated transcript is increased in bipolar disorder patients but decreased in schizophrenia patients. Moreover, the patients with schizophrenia with completed suicide or positive nicotine exposure showed significantly higher expression of GAD2 full length transcript. Alternative transcripts of GAD2 may be important in the growth and development of GABA-synthesizing neurons as well as abnormal GABA signaling in the DLPFC of patients with schizophrenia and affective disorders.

Genomic structure and expression of the human serotonin 2A receptor gene (HTR2A) locus: identification of novel HTR2A and antisense (HTR2A-AS1) exons

AbstractBackgroundThe serotonin 2A receptor is widely implicated in geneticn association studies and remains an important drug target for psychiatric,n neurological, and cardiovascular conditions. RNA sequencing redefined then architecture of the serotonin 2A receptor gene (HTR2A), revealing novel mRNA transcript isoforms utilizingn unannotated untranslated regions of the gene. Expression of these untranslatedn regions is modulated by common single nucleotide polymorphisms (SNPs), namelyn rs6311. Previous studies did not fully capture the complexity of the sense- andn antisense-encoded transcripts with respect to novel exons in the HTR2A gene locus. Here, we comprehensivelyn catalogued exons and RNA isoforms for both HTR2A and HTR2A-AS1 usingn RNA-Seq from human prefrontal cortex and multiple mouse tissues. We subsequentlyn tested associations between expression of newfound gene features and common SNPsn in humans.ResultsWe find that the human HTR2A genen spans ~66 kilobases and consists of 7, rather than 4 exons. Furthermore, then revised human HTR2A-AS1 gene spans ~474n kilobases and consists of 18, rather than 3 exons. Three HTR2A exons directly overlap with HTR2A-AS1 exons, suggesting potential for complementaryn nucleotide interactions. The repertoire of possible mouse Htr2a splice isoforms is remarkably similar ton humans and we also find evidence for overlapping sense-antisense transcripts inn the same relative positions as the human transcripts. rs6311 and SNPs in highn linkage disequilibrium are associated with HTR2A-AS1 expression, in addition to previously describedn associations with expression of the extended 5’ untranslated region of HTR2A.ConclusionsOur proposed HTR2A and HTR2A-AS1 gene structures dramatically differ fromn current annotations, now including overlapping exons on the sense and anti-sensen strands. We also find orthologous transcript isoforms expressed in mice,n providing opportunities to elucidate the biological roles of the human isoformsn using a model system. Associations between rs6311 and expression of HTR2A and HTR2A-AS1 suggest this polymorphism is capable of modulating then expression of the sense or antisense transcripts. Still unclear is whether thesen SNPs act directly on the expression of the sense or antisense transcripts andn whether overlapping exons are capable of interacting through complimentaryn base-pairing. Additional studies are necessary to determine the extent andn nature of interactions between the SNPs and the transcripts prior ton interpreting these findings in the context of phenotypes associated withn HTR2A.

Early Disruption of Corticolimbic Circuitry as a Model of Schizophrenia

The main problem with modeling schizophrenia has been a lack of knowledge about its etiology and basic neurobiology. This problem has precluded modeling aspects other than a rather limited number of phenomena. Most traditional models of schizophrenia reproduce primarily phenomena linked to dopamine, because the dopaminergic system has been strongly, although indirectly, implicated in this disorder (all effective antipsychotic drugs are antagonists of dopamine receptors, and dopamine agonists induce symptoms that resemble psychosis) (Kornetsky and Markowitz, 1978; McKinney and Moran, 1981; Ellenbroek and Cools, 1990; Costall and Naylor, 1995). Some dopamine-based models involve behavioral paradigms that were inspired by antipsychotic (i.e., antidopaminergic) pharmacology but bear no resemblance to schizophrenia (e.g., antagonism of apomorphine-induced emesis). Others reproduce phenomena analogous to selected features of schizophrenia such as motor behaviors (e.g., dopamimetic-induced stereotypies) and information processing deficits (e.g. apomorphine-induced prepulse inhibition of startle (PPI) abnormalities) (for review see, Costall and Naylor, 1995). These dopamine-linked behaviors, although not specific or unique for schizophrenia, can be at least detected and precisely evaluated in non-human species and were useful in screening drugs with a predicted mechanism of action (e.g., dopamine blockade). Their predictive validity might be expected given that the models were based on changing dopamine function.

Obstetric Risk Factors for Schizophrenia and Their Relationship to Genetic Predisposition

The literature on early life environmental risk factors for schizophrenia is a labyrinth of enormous extent, and it is growing. A literature search on obstetric and pregnancy complications and schizophrenia yields more than 1000 papers. In the arduous attempt to provide a compass, we have been struck by the tension between genes and early environment that is present throughout this literature. We do not promise to find the exit to the labyrinth, we only hope to show that following both threads will be necessary to start to understand the pathophysiology of the illness.

Role of gamma-amino-butyric acid in the dorsal anterior cingulate in age-associated changes in cognition

GABAergic mechanisms have been shown to contribute to cognitive aging in animal models, but there is currently limited in vivo evidence to support this relationship in humans. It is also unclear whether aging is associated with changes in GABA levels measured with proton magnetic resonance spectroscopy (MRS). Spectral-editing MRS at 3u2009T was used to measure GABA in the dorsal anterior cingulate cortex (dACC) for a large sample of healthy volunteers (Nu2009=u2009229) aged 18–55. In a subset of 171 participants, age effects on several cognitive tasks were studied. We formally tested whether the MRS measures mediated the relationship between age and cognition. Robust associations of age with performance were found for the Wisconsin Card Sorting Test ([WCST], pu2009<u20090.0001). Age was also significantly associated with declining levels of GABA in the dACC (pu2009<u20090.001), and GABA levels significantly predicted WCST performance (pu2009<u20090.0004). Mediation analysis revealed that GABA in the dACC mediated the effect of age on WCST performance (pu2009<u20090.01). Other metabolites were similarly associated with age, but only GABA and creatine levels were significantly associated with WCST performance. No association with age or cognitive performance was found in a frontal white matter control region in a subset of participants. The association of GABA with WCST performance was not related to the amount of brain atrophy associated with aging as measured by the proportion of CSF, gray, and white matter in the MRS voxel. These results implicate GABAergic and possibly energetic metabolism in the dACC as mechanisms of age effects in executive function.