Genetic variation in G72 correlates with brain activation in the right middle temporal gyrus in a verbal fluency task in healthy individuals

The D ‐amino acid oxidase activator gene (G72) has been found associated with several psychiatric disorders such as schizophrenia, major depression, and bipolar disorder. Impaired performance in verbal fluency tasks is an often replicated finding in the mentioned disorders. In functional neuroimaging studies, this dysfunction has been linked to signal changes in prefrontal and lateral temporal areas and could possibly constitute an endophenotype. Therefore, it is of interest whether genes associated with the disorders, such as G72, modulate verbal fluency performance and its neural correlates. Ninety‐six healthy individuals performed a semantic verbal fluency task while brain activation was measured with functional MRI. All subjects were genotyped for two single nucleotide polymorphisms (SNP) in the G72 gene, M23 (rs3918342) and M24 (rs1421292), that have previously shown association with the above‐mentioned disorders. The effect of genotype on brain activation was assessed with fMRI during a semantic verbal fluency task. Although there were no differences in performance, brain activation in the right middle temporal gyrus (BA 39 ) and the right precuneus (BA 7) was positively correlated with the number of M24 risk alleles in the G72 gene. G72 genotype does modulate brain activation during language production on a semantic level in key language areas. These findings are in line with structural and functional imaging studies in schizophrenia, which showed alterations in the right middle temporal gyrus. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.     

Interaction between effects of genes coding for dopamine and glutamate transmission on striatal and parahippocampal function

The genes for the dopamine transporter (DAT) and the D‐Amino acid oxidase activator (DAOA or G72) have been independently implicated in the risk for schizophrenia and in bipolar disorder and/or their related intermediate phenotypes. DAT and G72 respectively modulate central dopamine and glutamate transmission, the two systems most robustly implicated in these disorders. Contemporary studies have demonstrated that elevated dopamine function is associated with glutamatergic dysfunction in psychotic disorders. Using functional magnetic resonance imaging we examined whether there was an interaction between the effects of genes that influence dopamine and glutamate transmission (DAT and G72) on regional brain activation during verbal fluency, which is known to be abnormal in psychosis, in 80 healthy volunteers. Significant interactions between the effects of G72 and DAT polymorphisms on activation were evident in the striatum, parahippocampal gyrus, and supramarginal/angular gyri bilaterally, the right insula, in the right pre‐/postcentral and the left posterior cingulate/retrosplenial gyri (P < 0.05, FDR‐corrected across the whole brain). This provides evidence that interactions between the dopamine and the glutamate system, thought to be altered in psychosis, have an impact in executive processing which can be modulated by common genetic variation. Hum Brain Mapp 34:2244–2258, 2013. © 2012 Wiley Periodicals, Inc.     

G72 gene is associated with susceptibility to methamphetamine psychosis

Methamphetamine psychosis is considered as one of the pharmacological models of schizophrenia, and a hyperdopaminergic one. However, many lines of experimental evidence indicate that glutamatergic signaling is also involved in development of methamphetamine psychosis. Several genes related to glutamate function, e.g. the DTNBP1, G72, and GRM3 genes, were shown to be associated with schizophrenia susceptibility. Recently, we found significant association of the DTNBP1 gene with methamphetamine psychosis. This finding prompted us to examine the G72 gene encoding the d-amino acid oxidase activator (DAOA), which metabolizes d-serine, an NMDA co-agonist, in methamphetamine psychosis. Six SNPs of the G72 gene, which previously showed significant association with schizophrenia, were analyzed in 209 patients with methamphetamine psychosis and 291 age- and sex-matched normal controls. One SNP of M22 (rs778293) showed a significant association with methamphetamine psychosis (genotype: p = 0.00016, allele: p = 0.0015). Two haplotypes G-A of M12 (rs3916965)-M15 (rs2391191) (p = 0.00024) and T-T of M23 (rs947267)-M24 (rs1421292) (p = 0.00085) also showed associations with methamphetamine psychosis. The present findings suggest that the G72 gene may contribute to a predisposition to not only schizophrenia but also to methamphetamine psychosis.     

Association between the DAOA/G72 gene and bipolar disorder and meta-analyses in bipolar disorder and schizophrenia

Müller DJ, Zai CC, Shinkai T, Strauss J, Kennedy JL. Association between the DAOA/G72 gene and bipolar disorder and meta‐analyses in bipolar disorder and schizophrenia.
Bipolar Disord 2011: 13: 198–207. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objective: The d ‐amino acid oxidase activator (DAOA, or G72) is involved in the oxidation of d ‐serine, an endogenous modulator of N‐methyl‐d ‐aspartate receptors and thus represents an important candidate in psychotic disorders. Several studies reported the DAOA/G72 gene to be associated with schizophrenia (SZ) and bipolar disorder (BD); however, the associated polymorphisms varied between SZ and BD. This study attempts to replicate the DAOA/G72 findings in BD and to conduct subgroup analyses based on the presence or absence of psychotic symptoms. Methods: Five polymorphisms of the DAOA/G72 gene (rs1341402, rs1935062, rs2391191, rs947267, and rs778294) were analysed for association with BD in a family‐based study design (303 core families including 916 individuals). We also conducted a meta‐analysis of DAOA/G72 polymorphisms in BD and SZ. Results: Marker rs1935062 was significantly associated with BD diagnosis in our sample (Z‐score for C‐allele = ?2.33, p = 0.02, uncorrected for genome‐wide multiple comparisons). When we examined the subset of BD patients with psychotic symptoms (157 families), no significant results were obtained. Our meta‐analysis yielded negative findings for DAOA/G72 markers in BD and positive findings for marker rs2391191 in SZ in East Asians. However, significant heterogeneity across studies limits interpretation. Conclusions: Our results provide evidence that suggests a possible role of the DAOA/G72 gene in BD and SZ. Marker rs1935062 may be specifically associated with BD, while marker rs2391191 may be associated with SZ but not with BD. Together with previous studies, these findings suggest that the DAOA/G72 gene confers susceptibility to both BD and SZ, but that different polymorphisms may potentially differentiate between these two disorders.     

Increased excitatory amino acid transport into murine prion protein knockout astrocytes cultured in vitro

Prion protein (PrP) is expressed on a wide variety of cells and plays an important role in the pathogenesis of transmissible spongiform encephalopathies. However, its normal function remains unclear. Mice that do not express PrP exhibit deficits in spatial memory and abnormalities in excitatory neurotransmission suggestive that PrP may function in the glutamatergic synapse. Here, we show that transport of D ‐aspartate, a nonmetabolized L ‐glutamate analog, through excitatory amino acid transporters (EAATs) was faster in astrocytes from PrP knockout (PrPKO) mice than in astrocytes from C57BL/10SnJ wild‐type (WT) mice. Experiments using EAAT subtype‐specific inhibitors demonstrated that in both WT and PrPKO astrocytes, the majority of transport was mediated by EAAT1. Furthermore, PrPKO astrocytes were more effective than WT astrocytes at alleviating L ‐glutamate‐mediated excitotoxic damage in both WT and PrPKO neuronal cultures. Thus, in this in vitro model, PrPKO astrocytes exerted a functional influence on neuronal survival and may therefore influence regulation of glutamatergic neurotransmission in vivo. © 2011 Wiley‐Liss, Inc.     

Partial support for ZNF804A genotype‐dependent alterations in prefrontal connectivity

Genome‐wide association studies identified the single nucleotide polymorphism rs1344706 in ZNF804A as a common risk‐variant for schizophrenia and bipolar disorder. Whereas the molecular function of ZNF804A is yet unclear, recent imaging genetics studies have started to characterize the neural systems architecture linking rs1344706 genotype to psychosis. Carring rs1344706 risk‐alleles was associated with a decrease in functional connectivity within the dorsolateral prefrontal cortices (DLPFCs) as well as an increase in connectivity between the DLPFC and the hippocampal formation (HF) in the context of a working memory task. The present study aimed at replicating these findings in an independent sample of 94 healthy subjects. Subjects were genotyped for rs1344706 and performed a working memory task during functional magnetic resonance imaging. Results indicate no support for a decrease of functional coupling between the bilateral DLPFCs at higher ZNF804A risk status. However, the current data show the previously described alteration in functional coupling between the right DLPFC and the HFs, albeit with weaker effects. Decoupled by default, the functional connectivity between the right DLPFC and anterior HFs increased with the number of rs1344706 risk alleles. The present data support fronto‐hippocampal dysconnectivity as intermediate phenotype linking rs1344706 genotype to psychosis. We discuss the issues in replicating the interhemispheric DLPFC coupling in light of the effect sizes rs1344706 genotype has on brain function, concluding that further independent replication studies are fundamentally needed to ascertain the role of rs1344706 in the functional integration of neural systems. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

Brain changes following four weeks of unimanual motor training: Evidence from fMRI‐guided diffusion MRI tractography

We have reported reliable changes in behavior, brain structure, and function in 24 healthy right‐handed adults who practiced a finger‐thumb opposition sequence task with their left hand for 10 min daily, over 4 weeks. Here, we extend these findings by using diffusion MRI to investigate white‐matter changes in the corticospinal tract, basal‐ganglia, and connections of the dorsolateral prefrontal cortex. Twenty‐three participant datasets were available with pre‐training and post‐training scans. Task performance improved in all participants (mean: 52.8%, SD: 20.0%; group P < 0.01 FWE) and widespread microstructural changes were detected across the motor system of the “trained” hemisphere. Specifically, region‐of‐interest‐based analyses of diffusion MRI (n = 22) revealed significantly increased fractional anisotropy (FA) in the right caudate nucleus (4.9%; P < 0.05 FWE), and decreased mean diffusivity in the left nucleus accumbens (?1.3%; P < 0.05 FWE). Diffusion MRI tractography (n = 22), seeded by sensorimotor cortex fMRI activation, also revealed increased FA in the right corticospinal tract (mean 3.28%; P < 0.05 FWE) predominantly reflecting decreased radial diffusivity. These changes were consistent throughout the entire length of the tract. The left corticospinal tract did not show any changes. FA also increased in white matter connections between the right middle frontal gyrus and both right caudate nucleus (17/22 participants; P < 0.05 FWE) and right supplementary motor area (18/22 participants; P < 0.05 FWE). Equivalent changes in FA were not seen in the left (non‐trained) hemisphere. In combination with our functional and structural findings, this study provides detailed, multifocal evidence for widespread neuroplastic changes in the human brain resulting from motor training. Hum Brain Mapp 38:4302–4312, 2017 . © 2017 Wiley Periodicals, Inc.     

The effects of the glutamate antagonist memantine on brain activation to an auditory perception task

Glutamate is critically involved in the regulation of cognitive functions in humans. There is, however, sparse evidence regarding how blocking glutamate action at the receptor site during a cognitive task affects brain activation. In the current study, the effects of the glutamate antagonist memantine were examined with functional magnetic resonance imaging (fMRI). Thirty‐one healthy adults were scanned twice in a counter‐balanced design, either in a no‐drug session or after administration of memantine for 21 days. The subjects performed a simple auditory perception task with consonant‐vowel stimuli. Group‐level spatial independent component analysis (ICA) was used to decompose the data and to extract task‐related activations. The focus was on four task‐related ICA components with frontotemporal localization. The results showed that glutamate‐blockage resulted in a significant enhancement in one component, with no significant effect in the other three components. The enhanced effect of memantine was in the middle temporal gyrus, superior frontal gyrus, and middle frontal gyrus. It is suggested that the results reflect effects of glutamatergic processes primarily through non‐N‐methyl‐D ‐aspartate (NMDA) receptor pathways. Moreover, the results demonstrate that memantine can be used as a probe which allows for studying the effect of excitatory neurotransmission on neuronal activation. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

In vivo [123I]CNS‐1261 binding to D‐serine‐activated and MK801‐blocked NMDA receptors: A storage phosphor imaging study in rats

Disturbances of activity of the glutamatergic neurotransmitter system in the brain are present in many neuropsychiatric disorders. The N‐methyl‐D ‐aspartate (NMDA) receptor is the most abundant receptor of the glutamatergic system. In the neurodegenerative events of Alzheimer's disease, excessive activation of NMDA receptors may contribute to neuronal death. Inhibition of NMDA receptor activation may have neuroprotective effects and (semi)quantitative imaging of the activated system may help in the selection of patients for such inhibition therapies. In this study we evaluated [¹²³I]CNS‐1261 binding in the rat brain. This radiotracer binds in vivo to the MK801 binding site of activated NMDA receptors. To determine the optimal time point for ex vivo assessments after bolus injection [¹²³I]CNS‐1261 binding in rats, we performed a time course biodistribution study using dissection techniques. [¹²³I]CNS‐1261 binding was also studied in the rat brain using autoradiography by means of storage phosphor imaging, with prior facilitation of NMDA receptor activation by injection of the potent coagonist D ‐serine and after blocking of the NMDA receptor binding site by MK801 injection in D ‐serine pretreated rats. Measurements of [¹²³I]CNS‐1261 uptake matched the distribution of similar tracers for the MK801 binding site of the NMDA receptor and revealed an optimal time point of 2 h post injection for the assessment of tracer distribution in the rat brain. The blocking experiments indicated specific binding of [¹²³I]CNS‐1261 to NMDA receptors but also a considerable amount of nonspecific binding. Facilitation of NMDA receptor activation by D ‐serine did not result in an enhancement of binding of the radiotracer in the NMDA receptor‐rich rat hippocampus compared to the untreated group, as measured by autoradiography. In conclusion, our study has shown that [¹²³I]CNS‐1261 binding is influenced by NMDA receptor availability. However, high nonspecific binding limits quantification and small changes in receptor availability are unlikely to be detected. Synapse 63:557–564, 2009. © 2009 Wiley‐Liss, Inc.     

DAOA/G72 predicts the progression of prodromal syndromes to first episode psychosis

The genetic factors determining the progression of prodromal syndromes to first episode schizophrenia have remained enigmatic to date. In a unique prospective multicentre trial, we assessed whether variants at the d-amino acid oxidase activator (DAOA)/G72 locus influence progression to psychosis. Young subjects with a prodromal syndrome were observed prospectively for up to 2 years to assess the incidence of progression to schizophrenia or first episode psychosis. Of the 82 probands with a prodromal syndrome, 21 probands experienced progression to psychosis within the observation period. Assessment of nine common variants in the DAOA/G72 locus yielded two variants with the predictive value for symptom progression: all four probands with the rs1341402 CC genotype developed psychosis compared with 17 out of 78 probands with the TT or CT genotypes (χ² = 12.348; df = 2; p = 0.002). The relative risk for progression to psychosis was significantly increased in the CC genotype: RR = 4.588 (95% CI = 2.175–4.588). Similarly, for rs778294, 50% of probands with the AA genotype, but only 22% of probands with a GG or GA genotype progressed to psychosis (χ² = 7.027; df = 2; p = 0.030). Moreover, haplotype analysis revealed a susceptibility haplotype for progression to psychosis. This is one of the first studies to identify a specific genetic factor for the progression of prodromal syndromes to schizophrenia, and further underscores the importance of the DAOA/G72 gene for schizophrenia.     

Association of rs1006737 in CACNA1C with alterations in prefrontal activation and fronto‐hippocampal connectivity

Background: Genome‐wide association studies have identified the rs1006737 single nucleotide polymorphism (SNP) in the CACNA1C gene as a susceptibility locus for schizophrenia and bipolar disorder. On the neural systems level this association is explained by altered functioning of the dorsolateral prefrontal cortex (DLPFC) and the hippocampal formation (HF), brain regions also affected by mental illness. In the present study we investigated the association of rs1006737 genotype with prefrontal activation and fronto‐hippocampal connectivity. Methods: We used functional magnetic resonance imaging to measure neural activation during an n‐back working memory task in 94 healthy subjects. All subjects were genotyped for the SNP rs1006737. We tested associations of the rs1006737 genotype with changes in working‐memory‐related DLPFC activation and functional integration using a seed region functional connectivity approach. Results: Rs1006737 genotype was associated with altered right‐hemispheric DLPFC activation. The homozygous A (risk) group showed decreased activation compared to G‐allele carriers. Further, the functional connectivity analysis revealed a positive association of fronto‐hippocampal connectivity with rs1006737 A alleles. Conclusions: We did not replicate the previous findings of increased right DLPFC activation in CACNA1C rs1006737 A homozygotes. In fact, we found the opposite effect, thus questioning prefrontal inefficiency as rs1006737 genotype‐related intermediate phenotype. On the other hand, our results indicate that alterations in the functional coupling between the prefrontal cortex and the medial temporal lobe could represent a neural system phenotype that is mediated by CACNA1C rs1006737 and other genetic susceptibility loci for schizophrenia and bipolar disorder. Hum Brain Mapp 35:1190–1200, 2014. © 2013 Wiley Periodicals, Inc.     

Distinct and opposite profiles of connectivity during self‐reference task and rest in youth at clinical high risk for psychosis

Self‐reference is impaired in psychotic disorders such as schizophrenia, associated with disability, and closely related to characteristic patterns of aberrant brain connectivity. However, at present, it is unclear whether self‐reference is impacted in pathogenesis of the disorder. Alterations in connectivity during a self‐reference task or resting‐state in the psychosis risk (i.e., prodromal) period may yield important clues for biomarker development, as well as for novel treatment targets. This study examined a task‐based and resting‐state functional magnetic resonance imaging in individuals at clinical high risk (CHR) for psychosis (n = 22) and healthy control unaffected peers (n = 20). The self‐reference task comprised three task conditions where subjects were asked if an adjective was relevant to themselves (self), a designated other individual (other), or to evaluate the word's spelling (letter). Connectivity analyses examined medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC), regions commonly found in conjunction analyses of self‐reference, during both the self‐reference task and rest. In task connectivity analyses, CHR individuals exhibited decreased mPFC–PCC connectivity when compared to controls. In resting‐state analyses, CHR participants showed greater mPFC–PCC connectivity. Taken together, results suggest that psychosis‐like alterations in mPFC–PCC connectivity is present prior to psychosis onset across both task and rest.     

Early‐life‐stress affects the homeostasis of glutamatergic synapses

Early‐life stress induces several neuropsychological disorders in adulthood, including depression. Such disorders may be induced by functional alteration of the glutamatergic system. However, their underlying mechanisms have not yet been fully clarified. Furthermore, the involvement of glucocorticoids, which are representative stress hormones, has not yet been fully clarified. In this study, we used maternal deprivation (MD) mice as an early‐life‐stress model, and studied the changes in the glutamatergic system in adulthood. The glutamate concentration and neuronal activity in the somatosensory cortex (SSC) increased under basal conditions in MD mice. Stressful physical stimulation (SPS) increased the concentration of corticosterone, but not of glutamate, in the control mouse SSC. On the other hand, in the MD mice, although the basal concentration of corticosterone in the SSC increased, no SPS‐induced increase was observed. In contrast, the concentration of glutamate increased greatly during SPS. It was significantly high for 30 min after stimulation. The expression level of α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid/N‐methyl‐d ‐aspartate receptors in the MD mice was also changed compared with that in the control mice after stimulation. These findings indicate that early‐life stress disrupts the homeostasis of glutamatergic synapses.     

Activation of α1‐adrenoceptors enhances excitatory synaptic transmission via a pre‐ and postsynaptic protein kinase C‐dependent mechanism in the medial prefrontal cortex of rats

The physiological effects of α1‐adrenoceptors (α1‐ARs) have been examined in many brain regions. However, little is known about the mechanism of modulation on synaptic transmission by α1‐ARs in the medial prefrontal cortex (mPFC). The present study investigated how α₁‐AR activation regulates glutamatergic synaptic transmission in layer V/VI pyramidal cells of the rat mPFC. We found that the α₁‐AR agonist phenylephrine (Phe) induced a significant enhancement of the amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs). The facilitation effect of Phe on the frequency of mEPSCs involved a presynaptic protein kinase C‐dependent pathway. Phe produced a significant enhancement on the amplitude of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPA‐R)‐ and N‐methyl‐d ‐aspartic acid receptor (NMDA‐R)‐mediated evoked excitatory postsynaptic currents (eEPSCs). Phe enhanced inward currents evoked by puff application of glutamate or NMDA. The Phe‐induced facilitation of AMPA‐R‐ and NMDA‐R‐mediated eEPSCs required, in part, postsynaptic G_q, phospholipase C and PKC. These findings suggest that α₁‐AR activation facilitates excitatory synaptic transmission in mPFC pyramidal cells via both pre‐ and post‐synaptic PKC‐dependent mechanisms.     

d‐amino acid oxidase knockout (Dao−/−) mice show enhanced short‐term memory performance and heightened anxiety,but no sleep or circadian rhythm disruption

d ‐amino acid oxidase (DAO, DAAO) is an enzyme that degrades d ‐serine, the primary endogenous co‐agonist of the synaptic N‐methyl‐d ‐aspartate receptor. Convergent evidence implicates DAO in the pathophysiology and potential treatment of schizophrenia. To better understand the functional role of DAO, we characterized the behaviour of the first genetically engineered Dao knockout (Dao^?/?) mouse. Our primary objective was to assess both spatial and non‐spatial short‐term memory performance. Relative to wildtype (Dao^+/+) littermate controls, Dao^?/? mice demonstrated enhanced spatial recognition memory performance, improved odour recognition memory performance, and enhanced spontaneous alternation in the T‐maze. In addition, Dao^?/? mice displayed increased anxiety‐like behaviour in five tests of approach/avoidance conflict: the open field test, elevated plus maze, successive alleys, light/dark box and novelty‐suppressed feeding. Despite evidence of a reciprocal relationship between anxiety and sleep and circadian function in rodents, we found no evidence of sleep or circadian rhythm disruption in Dao^?/? mice. Overall, our observations are consistent with, and extend, findings in the natural mutant ddY/Dao^? line. These data add to a growing body of preclinical evidence linking the inhibition, inactivation or deletion of DAO with enhanced cognitive performance. Our results have implications for the development of DAO inhibitors as therapeutic agents.     

Facilitation of glutamate release from rat cerebral cortex nerve terminal by subanesthetic concentration propofol

Propofol is now the most commonly used intravenous anesthetic‐for general anesthesia and sedation because of its rapid onset and recovery. Besides the well‐known adverse effects of cardiovascular and respiratory depression, recent studies indicate that propofol may cause excitatory phenomena such as myoclonus, opisthotonus, and even seizure. However, the mechanisms of these excitatory effects of propofol have not been elucidated. Considering glutamate as the principle excitatory neurotransmitter in the central nervous system and excessive glutamatergic synaptic transmission can cause seizure, we examined the effect of propofol on the release of glutamate from rat cerebral cortex nerve terminals (synaptosomes). Results showed that subanesthetic concentration propofol facilitated 4‐aminopyridine (4‐AP), but not KCl‐ or ionomycin‐evoked glutamate release from nerve terminals. The facilitation of 4‐AP‐evoked glutamate release by propofol also occurred in the calcium chelation and significantly attenuated by glutamate transporter inhibitors, DL ‐threo‐β‐benzyloxyaspartic acid (DL ‐TBOA) and L ‐trans‐pyrrolidine‐2,4‐dicarboxylic acid (L ‐trans‐PDC). In addition, propofol increased 4‐AP‐evoked depolarization of the plasma membrane potential. Furthermore, protein kinase C (PKC) inhibition suppressed propofol‐mediated facilitation of glutamate release. These results suggest that subanesthetic concentration propofol facilitates glutamate release from rat cerebrocortical glutamatergic terminals by increasing nerve terminal excitability, likely through the activation of PKC pathway. This finding may provide an explanation for propofol‐induced excitatory phenomena. Synapse 63:773–781, 2009. © 2009 Wiley‐Liss, Inc.     

Mechanisms of status epilepticus: α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor hypothesis

Prolonged seizures of status epilepticus (SE) result from failure of mechanisms of seizure termination or activation of mechanisms that sustain seizures. Reduced γ‐aminobutyric acid type A receptor–mediated synaptic transmission contributes to impairment of seizure termination. However, mechanisms that sustain prolonged seizures are not known. We propose that insertion of GluA1 subunits at the glutamatergic synapses causes potentiation of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic receptor (AMPAR)‐mediated neurotransmission, which helps to spread and sustain seizures. The AMPAR‐mediated neurotransmission of CA1 pyramidal neurons was increased in animals in SE induced by pilocarpine. The surface membrane expression of GluA1 subunit–containing AMPARs on CA1 pyramidal neurons was also increased. Blockade of N‐methyl‐d ‐aspartate receptors 10 minutes after the onset of continuous electrographic seizure activity prevented the increase in the surface expression of GluA1 subunits. N‐methyl‐d ‐aspartate receptor antagonist MK‐801 in conjunction with diazepam also terminated seizures that were refractory to MK‐801 or diazepam alone. Future studies using mice lacking the GluA1 subunit expression will provide further insights into the role of GluA1 subunit–containing AMPAR plasticity in sustaining seizures of SE.     

Modulation of amygdala reactivity following rapidly acting interventions for major depression

Electroconvulsive therapy (ECT) and ketamine treatment both induce rapidly acting antidepressant effects in patients with major depressive disorder unresponsive to standard treatments, yet their specific impact on emotion processing is unknown. Here, we examined the neural underpinnings of emotion processing within and across patients (N = 44) receiving either ECT (N = 17, mean age: 36.8, 11.0 SD) or repeated subanesthetic (0.5 mg/kg) intravenous ketamine therapy (N = 27, mean age: 37.3, 10.8 SD) using a naturalistic study design. MRI and clinical data were collected before (TP1) and after treatment (TP2); healthy controls (N = 31, mean age: 34.5, 13.5 SD) completed one MRI session (TP1). An fMRI face‐matching task probed negative‐ and positive‐valence systems. Whole‐brain analysis, comparing neurofunctional changes within and across treatment groups, targeted brain regions involved in emotional facial processing, and included regions‐of‐interest analysis of amygdala responsivity. Main findings revealed a decrease in amygdalar reactivity after both ECT and ketamine for positive and negative emotional face processing (p < .05 family wise‐error (FWE) corrected). Subthreshold changes were observed between treatments within the dorsolateral prefrontal cortex and insula (p < .005, uncorrected). BOLD change for positive faces in the inferior parietal cortex significantly correlated with overall symptom improvement, and BOLD change in frontal regions correlated with anxiety for negative faces, and anhedonia for positive faces (p < .05 FWE corrected). Both serial ketamine and ECT treatment modulate amygdala response, while more subtle treatment‐specific changes occur in the larger functional network. Findings point to both common and differential mechanistic upstream systems‐level effects relating to fast‐acting antidepressant response, and symptoms of anxiety and anhedonia, for the processing of emotionally valenced stimuli.     

Functional MRI registration with tissue‐specific patch‐based functional correlation tensors

Population studies of brain function with resting‐state functional magnetic resonance imaging (rs‐fMRI) rely on accurate intersubject registration of functional areas. This is typically achieved through registration using high‐resolution structural images with more spatial details and better tissue contrast. However, accumulating evidence has suggested that such strategy cannot align functional regions well because functional areas are not necessarily consistent with anatomical structures. To alleviate this problem, a number of registration algorithms based directly on rs‐fMRI data have been developed, most of which utilize functional connectivity (FC) features for registration. However, most of these methods usually extract functional features only from the thin and highly curved cortical grey matter (GM), posing great challenges to accurate estimation of whole‐brain deformation fields. In this article, we demonstrate that additional useful functional features can also be extracted from the whole brain, not restricted to the GM, particularly the white‐matter (WM), for improving the overall functional registration. Specifically, we quantify local anisotropic correlation patterns of the blood oxygenation level‐dependent (BOLD) signals using tissue‐specific patch‐based functional correlation tensors (ts‐PFCTs) in both GM and WM. Functional registration is then performed by integrating the features from different tissues using the multi‐channel large deformation diffeomorphic metric mapping (mLDDMM) algorithm. Experimental results show that our method achieves superior functional registration performance, compared with conventional registration methods.     

TCF4 sequence variants and mRNA levels are associated with neurodevelopmental characteristics in psychotic disorders

TCF4 is involved in neurodevelopment, and intergenic and intronic variants in or close to the TCF4 gene have been associated with susceptibility to schizophrenia. However, the functional role of TCF4 at the level of gene expression and relationship to severity of core psychotic phenotypes are not known. TCF4 mRNA expression level in peripheral blood was determined in a large sample of patients with psychosis spectrum disorders (n=596) and healthy controls (n=385). The previously identified TCF4 risk variants (rs12966547 (G), rs9960767 (C), rs4309482 (A), rs2958182 (T) and rs17512836 (C)) were tested for association with characteristic psychosis phenotypes, including neurocognitive traits, psychotic symptoms and structural magnetic resonance imaging brain morphometric measures, using a linear regression model. Further, we explored the association of additional 59 single nucleotide polymorphisms (SNPs) covering the TCF4 gene to these phenotypes. The rs12966547 and rs4309482 risk variants were associated with poorer verbal fluency in the total sample. There were significant associations of other TCF4 SNPs with negative symptoms, verbal learning, executive functioning and age at onset in psychotic patients and brain abnormalities in total sample. The TCF4 mRNA expression level was significantly increased in psychosis patients compared with controls and positively correlated with positive- and negative-symptom levels. The increase in TCF4 mRNA expression level in psychosis patients and the association of TCF4 SNPs with core psychotic phenotypes across clinical, cognitive and brain morphological domains support that common TCF4 variants are involved in psychosis pathology, probably related to abnormal neurodevelopment.