John L. Waddington

Rare chromosomal deletions and duplications increase risk of schizophrenia

Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73–90% (ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants (CNVs) have been identified in individual patients with schizophrenia and also in neurodevelopmental disorders, but large-scale genome-wide surveys have not been performed. Here we report a genome-wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high-density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15-fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single-occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo-cardio-facial syndrome, which includes psychotic symptoms in 30% of patients. Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome-wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome-wide and at specific loci.

Dopaminergic behaviour stereospecifically promoted by the D1 agonist R-SK & F 38393 and selectively blocked by the D1 antagonist SCH 23390

The selective D1 dopamine receptor agonist R-SK & F 38393 (20 mg/kg), but not its S-antipode, stereospecifically promoted episodes of prominent grooming behaviour. Typical stereotyped behaviour, such at that induced by apomorphine, was not seen. Grooming responses to 20 mg/kg R-SK & F 38393 were blocked by 0.1–0.5 mg/kg of the selective D1 antagonist SCH 23390 but not by 1.0–5.0 mg/kg of the selective D2 antagonist metoclopramide, while stereotyped behaviour induced by 0.5 mg/kg apomorphine was blocked by both antagonists. These results are consistent with certain individual dopaminergic behaviours such as grooming being mediated by D1 receptors. Other dopaminergic syndromes may involve complex functional interactions between D1 and D2 receptors.

Silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects

Temporal lobe epilepsy is a common, chronic neurological disorder characterized by recurrent spontaneous seizures. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate post-transcriptional expression of protein-coding mRNAs, which may have key roles in the pathogenesis of neurological disorders. In experimental models of prolonged, injurious seizures (status epilepticus) and in human epilepsy, we found upregulation of miR-134, a brain-specific, activity-regulated miRNA that has been implicated in the control of dendritic spine morphology. Silencing of miR-134 expression in vivo using antagomirs reduced hippocampal CA3 pyramidal neuron dendrite spine density by 21% and rendered mice refractory to seizures and hippocampal injury caused by status epilepticus. Depletion of miR-134 after status epilepticus in mice reduced the later occurrence of spontaneous seizures by over 90% and mitigated the attendant pathological features of temporal lobe epilepsy. Thus, silencing miR-134 exerts prolonged seizure-suppressant and neuroprotective actions; determining whether these are anticonvulsant effects or are truly antiepileptogenic effects requires additional experimentation.

Spontaneous orofacial movements induced in rodents by very long-term neuroleptic drug administration: phenomenology, pathophysiology and putative relationship to tardive dyskinesia.

While understanding of the major clinical and ethical issue of tardive dyskinesia would be greatly facilitated by the development of an isomorphic or homologous animal model, particularly in rodents, this has proved to be a highly contentious issue. The literature on orofacial function in rats administered neuroleptic drugs for substantial proportions of their adult lifespan is reviewed. It reveals the emergence of late-onset orofacial movements in a number of studies, but very early-onset movements or no effect in others. Potential explantations for these discrepancies are considered, and ways of resolving such inconsistencies are suggested. The relationship of these various orofacial phenomena to dopaminergic and non-dopaminergic function, and to clinical syndromes, is critically evaluated.

Phenotypic characterization of spatial cognition and social behavior in mice with 'knockout' of the schizophrenia risk gene neuregulin 1.

Neuregulin-1 (NRG1) has been identified as a candidate susceptibility gene for schizophrenia. In the present study the functional role of the NRG1 gene, as it relates to cognitive and social processes known to be disrupted in schizophrenia, was assessed in mice with heterozygous deletion of transmembrane (TM)-domain NRG1 in comparison with wildtypes (WT). Social affiliative behavior was assessed using the sociability and preference for social novelty paradigm, in terms of time spent in: (i) a chamber containing an unfamiliar conspecific vs. an empty chamber (sociability), or (ii) a chamber containing an unfamiliar conspecific vs. a chamber containing a familiar conspecific (preference for social novelty). Social dominance and aggressive behavior were examined in the resident-intruder paradigm. Spatial learning and memory were assessed using the Barnes maze paradigm, while spatial working memory was measured using the continuous variant of the spontaneous alternation task. Barnes maze data revealed intact spatial learning in NRG1 mutants, with elevated baseline latency to enter the escape hole in male NRG1 mutants reflecting an increase in activity level. Similarly, although a greater number of overall arm entries were found, spontaneous alternation was unaffected in NRG1 mice. Social affiliation data revealed NRG1 mutants to evidence a specific loss of WT preference for spending time with an unfamiliar as opposed to a familiar conspecific. This suggests that NRG1 mutants show a selective impairment in response to social novelty. While spatial learning and working memory processes appear intact, heterozygous deletion of TM-domain NRG1 was associated with disruption to social novelty behavior. These data inform at a novel phenotypic level on the functional role of this gene in the context of its association with risk for schizophrenia.

Drugs acting on brain dopamine receptors: a conceptual re-evaluation five years after the first selective D-1 antagonist.

Neurochimie, neuro-anatomie et neurobiologie des recepteurs dopaminergiques D1 et D2: selectivite des medicaments in vivo et in vitro, caracteristiques moleculaires, localisation, effets du developpement et du vieillissement sur ces recepteurs, regulation. Etudes fonctionnelles des recepteurs D1 et D2 en utilisant des medicaments selectifs

The induction of grooming and vacuous chewing by a series of selective D-1 dopamine receptor agonists: two directions of D-1:D-2 interaction

A range of 3- and 6-substituted 1-phenyl-1H-3-benzazepine analogues of SK&F 38393 with D-1 agonist activity were compared for their behavioural effects in the intact adult rat and for their relative affinities for D-1 and D-2 dopamine receptors in vitro. All compounds showed selective affinity for D-1 receptors and induced prominent grooming behaviour, but those with the lower D-1:D-2 selectivity ratios also induced additional episodes of non-stereotyped sniffing, locomotion and rearing. No vacuous chewing was noted. There were marked differences in in vivo potency, extending over a 100-fold range. These responses to the most potent agonist, SK&F 77434 (3N-allyl-SK&F 38393) were reduced enantioselectively by the D-1 antagonist R-SK&F 83566. They were also reduced enantioselectively by the D-2 antagonist R-piquindone, but this pretreatment additionally released a marked vacuous chewing response to SK&F 77434. Prominent grooming may be a characteristic behavioural response to a range of D-1 agonists. It is suggested that there may be at least two forms of functional interaction between D-1 and D-2 systems, manifested concurrently in distinct elements of behaviour: one co-operative, as in the regulation of grooming, and with correlates in the regulation of pallidal neural activity; the other oppositional, as in the regulation of vacuous chewing, and with correlates in the regulation of striatal adenylate cyclase activity.

Effects of the putative D-1 antagonist SCH 23390 on stereotyped behaviour induced by the D-2 agonist RU24213

The effects of the putative selective dopamine D-1 antagonist benzazepine SCH 23390 and of the selective dopamine D-2 antagonist Ro22-2586 on stereotypy induced by the selective D-2 agonist RU24213 were compared. RU24213 (0.5–15 mg/kg) dose-dependently induced stereotyped behaviour characterised by continuous downward sniffing and locomotion. These responses were antagonised, as expected, by 40–200 μg/kg Ro22-2586, but surprisingly blocked by 40–200 μg/kg SCH 23390. The selectivities of these compounds for dopamine receptor subtypes were verified in terms of their relative abilities to displace the in vitro binding of 3H-piflutixol to striatal D-1 receptors and of 3H-spiperone to D-2 receptors. As SCH 23390 fails to influence D-2 mediated prolactin secretion or emesis in vivo, there appears to be no significant formation of an active metabolite of SCH 23390 with D-2 antagonist activity. Because SCH 23390 has some affinity for 5-hydroxytryptamine receptors, any effect on the serotonergic behavioural syndrome induced by 10 mg/kg 5-methoxy-N,N-dimethyltryptamine was also studied. The serotonergic responses of hind limb abduction, reciprocal forepaw treading and Straub tail were unaltered after 40–200 μg/kg SCH 23390, indicating no significant 5-HT blockade or non-specific depressant action at these doses which might influence the expression of stereotypy. Thus, these data are consistent with blockade of tonic D-1 dopaminergic activity that may influence the expression of behaviours initiated byD-2 dopaminergic stimulation.

Sniffing, rearing and locomotor responses to the D-1 dopamine agonist R-SK&F 38393 and to apomorphine: Differential interactions with the selective D-1 and D-2 antagonists SCH 23390 and metoclopramide

The D-1 agonist R-SK&F 38393 induced non-stereotyped sniffing, rearing and locomotor responses that were blocked by the D-1 antagonist SCH 23390. The D-2 antagonist metoclopramide failed to block sniffing but blocked rearing and locomotion. Stereotyped sniffing and locomotion induced by apomorphine were each blocked by both antagonists. Either the criteria by which compounds are designated as D-1 or D-2 selective agents require revision, or else D-1 and D-2 mechanisms are able to reciprocally interact to influence the expression of behaviour initiated by stimulation of either receptor subtype.

1H-magnetic resonance spectroscopy of the left temporal and frontal lobes in schizophrenia: Clinical, neurodevelopmental, and cognitive correlates ☆

Twenty eight schizophrenic patients and 20 normal volunteers underwent proton magnetic resonance spectroscopy (MRS) on the left temporal and frontal lobe regions. Male patients showed a significant reduction in frontal but not temporal n-acetylaspartate (an intraneuronally distributed metabolite) in comparison with either male controls or female patients; frontal choline was raised in male patients relative to these groups. Putative neurodevelopmental indices, including obstetric complications, family history of schizophrenia, and minor physical anomalies, proved unrelated to MRS resonances. However, multiple aspects of memory function in patients were related to temporal but not frontal creatine, a pattern that was not apparent among controls. These MRS findings complement some previous structural MRI studies and much clinical and epidemiological evidence of important gender differences in schizophrenia. The findings also suggest that memory dysfunction in patients with schizophrenia may be associated with a particular pattern of temporal lobe metabolism on MRS.