VGF function in depression and antidepressant efficacy.

Brain-derived neurotrophic factor (BDNF) is a critical effector of depression-like behaviors and antidepressant responses. Here, we show that VGF (non-acronymic), which is robustly regulated by BDNF/TrkB signaling, is downregulated in hippocampus (male/female) and upregulated in nucleus accumbens (NAc) (male) in depressed human subjects and in mice subjected to chronic social defeat stress (CSDS). Adeno-associated virus (AAV)-Cre-mediated Vgf ablation in floxed VGF mice, in dorsal hippocampus (dHc) or NAc, led to pro-depressant or antidepressant behaviors, respectively, while dHc- or NAc-AAV-VGF overexpression induced opposite outcomes. Mice with reduced VGF levels in the germ line (Vgf+/-) or in dHc (AAV-Cre-injected floxed mice) showed increased susceptibility to CSDS and impaired responses to ketamine treatment in the forced swim test. Floxed mice with conditional pan-neuronal (Synapsin-Cre) but not those with forebrain (αCaMKII-Cre) Vgf ablation displayed increased susceptibility to subthreshold social defeat stress, suggesting that neuronal VGF, expressed in part in inhibitory interneurons, regulates depression-like behavior. Acute antibody-mediated sequestration of VGF-derived C-terminal peptides AQEE-30 and TLQP-62 in dHc induced pro-depressant effects. Conversely, dHc TLQP-62 infusion had rapid antidepressant efficacy, which was reduced in BDNF floxed mice injected in dHc with AAV-Cre, and in NBQX- and rapamycin-pretreated wild-type mice, these compounds blocking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mammalian target of rapamycin (mTOR) signaling, respectively. VGF is therefore a critical modulator of depression-like behaviors in dHc and NAc. In hippocampus, the antidepressant response to ketamine is associated with rapid VGF translation, is impaired by reduced VGF expression, and as previously reported, requires coincident, rapid BDNF translation and release.

Magnetic resonance spectroscopy and tissue protein concentrations together suggest lower glutamate signaling in dentate gyrus in schizophrenia.

Hippocampal dysfunction in schizophrenia is widely acknowledged, yet the mechanism of such dysfunction remains debated. In this study we investigate the excitatory and inhibitory hippocampal neurotransmission using two complementary methodologies, proton magnetic resonance spectroscopy (MRS) and tissue biochemistry, sampling individuals with schizophrenia in vivo and postmortem hippocampal tissue in vitro. The results show significantly lower glutamate concentrations in hippocampus in schizophrenia, an in vivo finding mirrored by lower GluN1 protein levels selectively in the dentate gyrus (DG) in vitro. In a mouse model with a DG knockout of the GRIN1 gene, we further confirmed that a selective decrease in DG GluN1 is sufficient to decrease the glutamate concentrations in the whole hippocampus. Gamma-aminobutyric acid (GABA) concentrations and GAD67 protein were not significantly different in hippocampus in schizophrenia. Similarly, GABA concentrations in the hippocampi of mice with a DG knockout of the GRIN1 gene were not significantly different from wild type. These findings provide strong evidence implicating the excitatory system within hippocampus in the pathophysiology of schizophrenia, particularly indicating the DG as a site of pathology.

Resting-state brain function in schizophrenia and psychotic bipolar probands and their first-degree relatives.

BACKGROUND: Schizophrenia (SCZ) and psychotic bipolar disorder (PBD) share considerable overlap in clinical features, genetic risk factors and co-occurrence among relatives. The common and unique functional cerebral deficits in these disorders, and in unaffected relatives, remain to be identified. METHOD: A total of 59 healthy controls, 37 SCZ and 57 PBD probands and their unaffected first-degree relatives (38 and 28, respectively) were studied using resting-state functional magnetic resonance imaging (rfMRI). Regional cerebral function was evaluated by measuring the amplitude of low-frequency fluctuations (ALFF). Areas with ALFF alterations were used as seeds in whole-brain functional connectivity analysis. We then tested whether abnormalities identified in probands were present in unaffected relatives. RESULTS: SCZ and PBD probands both demonstrated regional hypoactivity in the orbital frontal cortex and cingulate gyrus, as well as abnormal connectivity within striatal-thalamo-cortical networks. SCZ probands showed greater and more widely distributed ALFF alterations including the thalamus and bilateral parahippocampal gyri. Increased parahippocampal ALFF was related to positive symptoms and cognitive deficit. PBD patients showed uniquely increased functional connectivity between the thalamus and bilateral insula. Only PBD relatives showed abnormal connectivity within striatal-thalamo-cortical networks seen in both proband groups. CONCLUSIONS: The present findings reveal a common pattern of deficits in frontostriatal circuitry across SCZ and PBD, and unique regional and functional connectivity abnormalities that distinguish them. The abnormal network connectivity in PBD relatives that was present in both proband groups may reflect genetic susceptibility associated with risk for psychosis, but within-family associations of this measure were not high.

Kv3.1-containing K(+) channels are reduced in untreated schizophrenia and normalized with antipsychotic drugs.

Neuronal firing is a fundamental element of cerebral function; and, voltage-gated potassium (K(+)) channels regulate that firing through the repolarization of action potentials. Kv3-type channels (Kv3.1-Kv3.4) represent a family of voltage-gated K(+) channels that have fast-spiking properties. Kv3.1 channel subunits are predominantly localized to cortical parvalbumin (PV)-positive, inhibitory interneurons. The firing properties of these interneurons participate in establishing the normal gamma oscillations and synchrony of cortical neuronal populations, thought to be the signature of higher information processing in human brain. Schizophrenia (SZ) is associated with abnormalities in cortical gamma synchrony and in information processing, particularly with dysfunction in working memory and executive function. Here, we report the distribution of Kv3.1b and Kv3.2 protein in normal human brain, showing that Kv3.1b is limited to neocortical areas, whereas Kv3.2 is abundantly represented in neo- and subcortical regions. In SZ cases, levels of Kv3.1b protein are decreased in the neocortex, but only in cases without antipsychotic drug (APD) treatment; Kv3.1 levels are normal in antipsychotic-treated cases. Kv3.2 is not different in distribution or in level between normal and SZ cases, nor influenced by APD, in any region tested. The apparent increase in Kv3.1b protein levels by APDs in SZ neocortex was confirmed in laboratory rodents treated with chronic APDs. These findings show a decrease in Kv3.1b channel protein in SZ neocortex, a deficit that is restored by APDs. This alteration could be fundamentally involved in the cortical manifestations of SZ and in the therapeutic response to APDs.

Emotional scene processing in biotypes of psychosis.

Social-emotional deficits in psychosis may be indexed by deviations in emotional scene processing, but event-related potential (ERP) studies indicate such deviations may not map cleanly to diagnostic categories. Neurobiologically defined psychosis subgroups offer an alternative that may better capture neurophysiological correlates of social-emotional deficits. The current study investigates emotional scene-elicited ERPs in Biotypes of psychosis in a large (N = 622), well-characterized sample. Electroencephalography was recorded in healthy persons (N = 129), Biotype-1 (N = 195), Biotype-2 (N = 131), and Biotype-3 (N = 167) psychosis cases. ERPs were measured from posterior and centroparietal scalp locations. Neural responses to emotional scenes were compared between healthy and psychosis groups. Multivariate group discrimination analyses resulted in two composite variates that differentiated groups. The first variate displayed large differences between low-cognition (Biotype-1, Biotype-2) and intact-cognition groups (Biotype-3, healthy persons). The second indicated a small-to-moderate distinction of Biotypes-2 and -3 from Biotype-1 and healthy persons. Two multivariate correlations were identified indicating associations between 1) self-reported emotional experience and generalized cognition and 2) socio-occupational functioning and late-stage emotional processing. Psychosis Biotypes displayed emotional processing deficits not apparent in DSM psychosis subgroups. Future translational research may benefit from exploring emotional scene processing in such neurobiologically-defined psychosis groups.

Schizophrenic symptoms improve with apomorphine.

Eighteen chronic schizophrenic patients received subcutaneous doses of apomorphine, a dopamine receptor agonist, and of placebo in separate trials. A significant improvement in psychotic symptoms occurred after apomorphine compared to placebo. The results are interpreted as a consequence of presynaptic dopamine receptor activation by apomorphine with a subsequent decrease in dopamine-mediated neural transmission.

Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics.

In postmortem studies of patients with schizophrenia, D2 dopamine receptors in the basal ganglia have been observed to be more numerous than in patients with no history of neurological or psychiatric disease. Because most patients with schizophrenia are treated with neuroleptic drugs that block D2 dopamine receptors in the caudate nucleus, it has been suggested that this increase in the number of receptors is a result of adaptation to these drugs rather than a biochemical abnormality intrinsic to schizophrenia. With positron emission tomography (PET), the D2 dopamine receptor density in the caudate nucleus of living human beings was measured in normal volunteers and in two groups of patients with schizophrenia--one group that had never been treated with neuroleptics and another group that had been treated with these drugs. D2 dopamine receptor densities in the caudate nucleus were higher in both groups of patients than in the normal volunteers. Thus, schizophrenia itself is associated with an increase in brain D2 dopamine receptor density.

Deviation from expected cognitive ability across psychotic disorders.

Patients with schizophrenia show a deficit in cognitive ability compared to estimated premorbid and familial intellectual abilities. However, the degree to which this pattern holds across psychotic disorders and is familial is unclear. The present study examined deviation from expected cognitive level in schizophrenia, schizoaffective disorder, and psychotic bipolar disorder probands and their first-degree relatives. Using a norm-based regression approach, parental education and WRAT-IV Reading scores (both significant predictors of cognitive level in the healthy control group) were used to predict global neuropsychological function as measured by the composite score from the Brief Assessment of Cognition in Schizophrenia (BACS) test in probands and relatives. When compared to healthy control group, psychotic probands showed a significant gap between observed and predicted BACS composite scores and a greater likelihood of robust cognitive decline. This effect was not seen in unaffected relatives. While BACS and WRAT-IV Reading scores were themselves highly familial, the decline in cognitive function from expectation had lower estimates of familiality. Thus, illness-related factors such as epigenetic, treatment, or pathophysiological factors may be important causes of illness related decline in cognitive abilities across psychotic disorders. This is consistent with the markedly greater level of cognitive impairment seen in affected individuals compared to their unaffected family members.

Stimulating and inhibitory effects of the dopamine "stabilizer" (-)-OSU6162 on dopamine D2 receptor function in vitro.

The effect of (-)-OSU6162 on the incorporation of GTPgammaS(35) in the membranes of hD(2l)-transfected CHO cells was investigated. In the absence of dopamine the compound exerted a slight but significant stimulating action, suggesting a weak partial agonism. In the presence of dopamine, low concentrations (10 to 100 nM) enhanced the stimulating action of dopamine. This enhancing effect was reversed by higher concentrations of (-)-OSU6162 in a complex biphasic manner. The dopamine-enhancing action is proposed to be mediated by binding to an allosteric site with high affinity and the inhibitory component by a low-affinity binding to the orthosteric site of the dopamine receptor.

Genome-wide association studies of smooth pursuit and antisaccade eye movements in psychotic disorders: findings from the B-SNIP study.

Eye movement deviations, particularly deficits of initial sensorimotor processing and sustained pursuit maintenance, and antisaccade inhibition errors, are established intermediate phenotypes for psychotic disorders. We here studied eye movement measures of 849 participants from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study (schizophrenia N=230, schizoaffective disorder N=155, psychotic bipolar disorder N=206 and healthy controls N=258) as quantitative phenotypes in relation to genetic data, while controlling for genetically derived ancestry measures, age and sex. A mixed-modeling genome-wide association studies approach was used including ~4.4 million genotypes (PsychChip and 1000 Genomes imputation). Across participants, sensorimotor processing at pursuit initiation was significantly associated with a single nucleotide polymorphism in IPO8 (12p11.21, P=8 × 10-11), whereas suggestive associations with sustained pursuit maintenance were identified with SNPs in SH3GL2 (9p22.2, P=3 × 10-8). In participants of predominantly African ancestry, sensorimotor processing was also significantly associated with SNPs in PCDH12 (5q31.3, P=1.6 × 10-10), and suggestive associations were observed with NRSN1 (6p22.3, P=5.4 × 10-8) and LMO7 (13q22.2, P=7.3x10-8), whereas antisaccade error rate was significantly associated with a non-coding region at chromosome 7 (P=6.5 × 10-9). Exploratory pathway analyses revealed associations with nervous system development and function for 40 top genes with sensorimotor processing and pursuit maintenance (P=4.9 × 10-2-9.8 × 10-4). Our findings suggest novel patterns of genetic variation relevant for brain systems subserving eye movement control known to be impaired in psychotic disorders. They include genes involved in nuclear trafficking and gene silencing (IPO8), fast axonal guidance and synaptic specificity (PCDH12), transduction of nerve signals (NRSN1), retinal degeneration (LMO7), synaptic glutamate release (SH3GL2), and broader nervous system development and function.

Unitary construct of generalized cognitive ability underlying BACS performance across psychotic disorders and in their first-degree relatives.

Despite robust evidence of neurocognitive dysfunction in psychotic patients, the degree of similarity in cognitive architecture across psychotic disorders and among their respective first-degree relatives is not well delineated. The present study examined the latent factor structure of the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery. Analyses were conducted on 783 psychosis spectrum probands (schizophrenia, schizoaffective, psychotic bipolar), 887 of their first-degree relatives, and 396 non-psychiatric controls from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium. Exploratory factor analysis of BACS subtest scores indicated a single-factor solution that was similar across all groups and provided the best overall data fit in confirmatory analyses. Correlations between the standard BACS composite score and the sum of subscale scores weighted by their loadings on this unitary factor were very high in all groups (r≥.99). Thus, the BACS assesses a similar unitary cognitive construct in probands with different psychotic disorders, in their first-degree relatives, and in healthy controls, and this factor is well measured by the test's standard composite score.

Improvement in tardive dyskinesia after muscimol therapy.

Muscimol, thought to be a agonist of gamma-aminobutyric acid (GABA), was administered to eight neuroleptic-free subjects with tardive dyskinesia. At oral dose levels from 5 to 9 mg, involuntary movements were consistently attenuated, usually in the absence of sedation. These results support the view that pharmacologic attempts to stimulate GABA-mediated synaptic transmission may afford symptomatic relief to patients with tardive dyskinesia.

A neuroendocrine study of supersensitivity in tardive dyskinesia.

A study of the tuberoinfundibular dopamine tract was undertaken in chronic schizophrenic patients with and without tardive dyskinesia. Biochemical evidence of the purported dopamine receptor supersensitivity in tardive dyskinesia was sought by demonstrating a hyperresponse of growth hormone and prolactin to dopamine agonists. Contrary to this prediction, no endocrine supersensitivity occurred in the tardive dyskinesia patients. Rather, a significantly decreased response to dopaminergic stimulation was demonstrated in the total chronic schizophrenic group.

Des-tyrosine-gamma-endorphin administration in chronic schizophrenics. A preliminary report.

The beta-lipotrophin fragment des-tyrosine-gamma-endorphin (DT gamma E) has been reported to have antipsychotic properties. We administered the compound without other psychoactive drugs to a subpopulation of schizophrenic subjects. Male patients with chronic psychotic illness and previous long-term neuroleptic therapy were given DT gamma E at a similar dose and duration of treatment that have been reported to be effective. No improvement in psychotic symptoms occurred; plasma prolactin level, a parameter characteristically altered by neuroleptic treatment, did not change. The beneficial effects of DT gamma E in schizophrenia may be specific to a diagnostic category, may be dependent on past pharmacologic treatment, or may occur only in combination with other drugs.

Brain gamma-aminobutyric acid abnormality in tardive dyskinesia. Reduction in cerebrospinal fluid GABA levels and therapeutic response to GABA agonist treatment.

A double-blind, placebo-controlled trial of gamma-vinyl gamma-aminobutyric acid (GVG) and 4,5,6,7-tetrahydroisoxazolo-(5,4-c) pyridine-3-ol (THIP) was carried out in drug-free schizophrenic patients with tardive dyskinesia. A significant decrease in dyskinetic symptoms occurred with the administration of GVG, associated with a twofold increase in cerebrospinal fluid levels of GABA; THIP produced a more moderate, yet consistent decrease in the involuntary movements. A pathophysiologic role for gamma-aminobutyric acid (GABA)-mediated neuronal transmission in tardive dyskinesia was explored by analyzing cerebrospinal fluid GABA concentrations in drug-free schizophrenic patients with and without tardive dyskinesia. A significant reduction in cerebrospinal fluid levels of GABA was observed in the dyskinetic schizophrenics compared with the nondyskinetic controls. These data compliment a growing body of experimental evidence suggesting a critical role for GABA-ergic neurons in the pathophysiology of tardive dyskinesia.

Dopamine agonist treatment of schizophrenia with N-propylnorapomorphine.

We administered N-propylnorapomorphine, a potent aporphine-family dopamine (DA) agonist, to schizophrenic patients with active psychotic symptoms. After acute administration a significant antipsychotic action of N-propylnorapomorphine, maximal at an oral dose of 19 mg, was noted. The antipsychotic action predominated in subjects with neuroleptic-responsive symptoms, not in neuroleptic-nonresponders. However, when N-propylnorapomorphine was administered on a subchronic dosage schedule, no antipsychotic effect occurred. These observations suggest a rapid-onset tolerance phenomenon of psychosis to N-propylnorapomorphine and are consistent with results from preclinical experiments. These data support the idea that the acute antipsychotic response of DA agonists is mediated by the DA autoreceptor but fail to provide evidence for the potential clinical usefulness of this treatment approach.

Catching up on schizophrenia. The Fifth International Congress on Schizophrenia Research, Warm Springs, Va, April 8-12, 1995.

It is axiomatic that the diversity and ingenuity of strategies in the study of schizophrenia bear testimony to the complexity of this disorder. Accordingly, the opportunity for investigators of diverse interests to share their latest findings and be informed of developments in key areas of science is critical to advance our understanding of schizophrenia. Nearly 700 investigators from around the world gathered at Warm Springs, Va, to present their data at the Fifth International Congress on Schizophrenia Research (April 8-12, 1995). This 5-day conference, held every other year alternating with the European Winter Workshop on Schizophrenia, is co-organized by S. Charles Schulz, MD, Case Western Reserve University, Cleveland, Ohio, and Carol Tamminga, MD, Maryland Psychiatric Research Center, University of Maryland at Baltimore. Drs Schulz and Tamminga first held the Congress in 1987 in Clearwater, Fla, with 170 investigators presenting. The Congress has flourished since then and is now the largest research meeting devoted solely to schizophrenia. The Congress organizers, the program coordinator (Jeffrey Lieberman, MD, Hillside Hospital, Glen Oaks, NY), and the Congress coordinator (Susan Nusbaum, Maryland Psychiatric Research Center) are congratulated on the success of this event and its contribution to fostering initiatives and collaborations within schizophrenia research.

Limbic system abnormalities identified in schizophrenia using positron emission tomography with fluorodeoxyglucose and neocortical alterations with deficit syndrome.

A hypothesis of psychosis localization in schizophrenia was derived from studying metabolic alterations in rat brain in response to phencyclidine hydrochloride administration. Since phencyclidine and its selective agonist dizocilpine maleate (MK801) induced overlapping and long-lasting metabolic alterations predominantly in limbic areas, the hypothesis developed that schizophrenic patients with psychosis would evidence functional abnormalities in limbic circuits compared with normal controls. Accordingly, 12 actively psychotic, drug-free patients with schizophrenia and matched normal controls underwent functional brain scans using positron emission tomography and fluorodeoxyglucose. Regions of interest were identified on five matched axial slices in each patient and control subject, and average metabolic rates were calculated. Patients with schizophrenia showed a significantly lower regional cerebral metabolic rate of glucose in the hippocampus and the anterior cingulate cortex than did normal controls, but not in neocortical areas or in the extrapyramidal system. When the group of schizophrenic patients was divided into deficit and nondeficit types, a preliminary exploratory analysis suggested thalamic, frontal, and parietal cortical hypometabolism in the deficit subgroup, with normal metabolism in the nondeficit patient group in those areas; in contrast, hippocampal and anterior cingulate cortical metabolism was reduced in both deficit and nondeficit subtypes. These results suggest that the limbic system, especially the hippocampus, is functionally involved in schizophrenic psychosis and that different manifestations of schizophrenia may involve different neuronal circuits.

Schizophrenia: Evidence implicating hippocampal GluN2B protein and REST epigenetics in psychosis pathophysiology.

The hippocampus is strongly implicated in the psychotic symptoms of schizophrenia. Functionally, basal hippocampal activity (perfusion) is elevated in schizophrenic psychosis, as measured with positron emission tomography (PET) and with magnetic resonance (MR) perfusion techniques, while hippocampal activation to memory tasks is reduced. Subfield-specific hippocampal molecular pathology exists in human psychosis tissue which could underlie this neuronal hyperactivity, including increased GluN2B-containing NMDA receptors in hippocampal CA3, along with increased postsynaptic density protein-95 (PSD-95) along with augmented dendritic spines on the pyramidal neuron apical dendrites. We interpret these observations to implicate a reduction in the influence of a ubiquitous gene repressor, repressor element-1 silencing transcription factor (REST) in psychosis; REST is involved in the age-related maturation of the NMDA receptor from GluN2B- to GluN2A-containing NMDA receptors through epigenetic remodeling. These CA3 changes in psychosis leave the hippocampus liable to pathological increases in neuronal activity, feedforward excitation and false memory formation, sometimes with psychotic content.

Effects of lithium on cortical thickness and hippocampal subfield volumes in psychotic bipolar disorder.

Relative to healthy controls, lithium free bipolar patients exhibit significant gray matter abnormalities. Lithium, the long-time reference standard medication treatment for bipolar disorder, has been proposed to be neuro-protective against these abnormalities. However, its effects on cortical thickness and hippocampal subfield (HSF) volumes remain unstudied and unclear, respectively, in bipolar disorder. This study included 342 healthy controls (HC), 51 lithium free PBD patients (NoLi), and 51 PBD patients taking lithium (Li). Regional gray matter thickness and HSF volume values were extracted from 3T MRI images. After matching NoLi and Li samples, regions where HC differed from either Li or NoLi were identified. In regions of significant or trending HC-NoLi difference, Li-NoLi comparisons were made. No significant HC-Li thickness or HSF volume differences were found. Significantly thinner occipital cortices were observed in NoLi compared to HC. In these regions, Li consistently exhibited non-significant trends for greater cortical thickness relative to NoLi. Significantly less volume was observed in NoLi compared to both HC and Li in right HSFs. Our results suggest that PBD in patients not treated with Li is associated with thinner occipital cortices and reduced HSF volumes compared with HC. Patients treated with Li exhibited significantly larger HSF volumes than NoLi, and those treated with Li were no different from HC in cortical thickness or hippocampal volumes. This evidence directly supports the hypothesis that Li may counteract the locally thinner and smaller gray matter structure found in PBD.