Modeling neurodevelopmental cognitive deficits in tasks with cross-species translational validity.

Numerous psychiatric disorders whose cognitive dysfunction links to functional outcome have neurodevelopmental origins including schizophrenia, autism and bipolar disorder. Treatments are needed for these cognitive deficits, which require development using animal models. Models of neurodevelopmental disorders are as varied and diverse as the disorders themselves, recreating some but not all aspects of the disorder. This variety may in part underlie why purported procognitive treatments translated from these models have failed to restore functioning in the targeted patient populations. Further complications arise from environmental factors used in these models that can contribute to numerous disorders, perhaps only impacting specific domains, while diagnostic boundaries define individual disorders, limiting translational efficacy. The Research Domain Criteria project seeks to 'develop new ways to classify mental disorders based on behavioral dimensions and neurobiological measures' in hopes of facilitating translational research by remaining agnostic toward diagnostic borders derived from clinical presentation in humans. Models could therefore recreate biosignatures of cognitive dysfunction irrespective of disease state. This review highlights work within the field of neurodevelopmental models of psychiatric disorders tested in cross-species translational cognitive paradigms that directly inform this newly developing research strategy. By expounding on this approach, the hopes are that a fuller understanding of each model may be attainable in terms of the cognitive profile elicited by each manipulation. Hence, conclusions may begin to be drawn on the nature of cognitive neuropathology on neurodevelopmental and other disorders, increasing the chances of procognitive treatment development for individuals affected in specific cognitive domains.

Global quantitative analysis of phosphorylation underlying phencyclidine signaling and sensorimotor gating in the prefrontal cortex.

Prepulse inhibition (PPI) is an example of sensorimotor gating and deficits in PPI have been demonstrated in schizophrenia patients. Phencyclidine (PCP) suppression of PPI in animals has been studied to elucidate the pathological elements of schizophrenia. However, the molecular mechanisms underlying PCP treatment or PPI in the brain are still poorly understood. In this study, quantitative phosphoproteomic analysis was performed on the prefrontal cortex from rats that were subjected to PPI after being systemically injected with PCP or saline. PCP downregulated phosphorylation events were significantly enriched in proteins associated with long-term potentiation (LTP). Importantly, this data set identifies functionally novel phosphorylation sites on known LTP-associated signaling molecules. In addition, mutagenesis of a significantly altered phosphorylation site on xCT (SLC7A11), the light chain of system xc-, the cystine/glutamate antiporter, suggests that PCP also regulates the activity of this protein. Finally, new insights were also derived on PPI signaling independent of PCP treatment. This is the first quantitative phosphorylation proteomic analysis providing new molecular insights into sensorimotor gating.

Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy.

Autism spectrum disorders (ASDs) now affect 1-2% of the children born in the United States. Hundreds of genetic, metabolic and environmental factors are known to increase the risk of ASD. Similar factors are known to influence the risk of schizophrenia and bipolar disorder; however, a unifying mechanistic explanation has remained elusive. Here we used the maternal immune activation (MIA) mouse model of neurodevelopmental and neuropsychiatric disorders to study the effects of a single dose of the antipurinergic drug suramin on the behavior and metabolism of adult animals. We found that disturbances in social behavior, novelty preference and metabolism are not permanent but are treatable with antipurinergic therapy (APT) in this model of ASD and schizophrenia. A single dose of suramin (20 mg kg(-1) intraperitoneally (i.p.)) given to 6-month-old adults restored normal social behavior, novelty preference and metabolism. Comprehensive metabolomic analysis identified purine metabolism as the key regulatory pathway. Correction of purine metabolism normalized 17 of 18 metabolic pathways that were disturbed in the MIA model. Two days after treatment, the suramin concentration in the plasma and brainstem was 7.64 µM pmol µl(-1) (±0.50) and 5.15 pmol mg(-1) (±0.49), respectively. These data show good uptake of suramin into the central nervous system at the level of the brainstem. Most of the improvements associated with APT were lost after 5 weeks of drug washout, consistent with the 1-week plasma half-life of suramin in mice. Our results show that purine metabolism is a master regulator of behavior and metabolism in the MIA model, and that single-dose APT with suramin acutely reverses these abnormalities, even in adults.

Deficits in parvalbumin and calbindin immunoreactive cells in the hippocampus of isolation reared rats.

Post-mortem studies have provided evidence for abnormalities of the gamma-aminobutyric acid (GABA)-ergic system in schizophrenia. The calcium-binding proteins (CBPs), parvalbumin (PV), calbindin (CB) and calretinin (CR) can be used as markers for specific subpopulations of GABAergic neurons in the brain. Isolation rearing of rats is a non-pharmacological, non-lesion manipulation that leads to deficits in prepulse inhibition of the startle reflex (PPI) and other behavioural and neurochemical alterations reminiscent of schizophrenia. Female rats were reared in social housing (groups of three) or singly for 11 weeks post weaning and PPI was measured. Brains were removed and hippocampal CBP- containing neurons determined following immunocytochemical staining. Compared to socially housed rats, isolated rats exhibited PPI deficits and reductions in PV and CB-immunoreactive cells in the hippocampus, with no significant change in CR. These findings demonstrate selective abnormalities of sub-populations of GABAergic interneurons in the hippocampus of isolation reared rats, which resemble the neuronal deficits seen in this region in schizophrenia.

Autism as a disorder of neural information processing: directions for research and targets for therapy.

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which they feed, is hampered by the large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging, and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself.

Dopamine depletion of the nucleus accumbens reverses isolation-induced deficits in prepulse inhibition in rats.

Rearing rats in social isolation from weaning into adulthood leads to deficits in prepulse inhibition and alterations in monoamine systems that modulate prepulse inhibition. For example, rats reared in social isolation have elevated dopamine levels in the nucleus accumbens. Previous studies in rats have shown that nucleus accumbens dopamine depletion with 6-hydroxydopamine blocks the prepulse inhibition-disruptive effects of amphetamine, an indirect dopamine agonist. We tested the hypothesis that prepulse-inhibition deficits in isolation-reared rats are dependent on elevated dopamine levels in the nucleus accumbens. Specifically, we examined whether nucleus accumbens dopamine depletion would attenuate the isolation-induced disruption of prepulse inhibition. Isolation-housed female Long-Evans rats exhibited deficient prepulse inhibition. At 9 weeks post weaning, bilateral injections of 6-hydroxydopamine (8 microg/side) or ascorbic acid vehicle (0.1%) into the nucleus accumbens of social and isolation-reared rats were performed (8-10 rats per group). One week after surgery, prepulse inhibition deficits were exhibited by isolation-reared rats that received vehicle infusion into the nucleus accumbens, but not by those that received 6-hydroxydopamine infusions into the nucleus accumbens. 6-Hydroxydopamine infusions did not significantly change prepulse inhibition in socially reared rats. Behavioral and neurochemical evidence of nucleus accumbens dopamine depletion included: 1) a blockade of amphetamine-stimulated locomotor activity in nucleus accumbens 6-hydroxydopamine-infused isolated and socially reared rats; and 2) high performance liquid chromatography measurements demonstrating a significant depletion of accumbens dopamine and its major metabolites, in addition to decreases in dopamine, homovanillic acid, and 3,4-dihydroxyphenylacetic acid levels in the frontal cortex and anterior caudate. These data indicate that dopamine in the nucleus accumbens plays an essential role in the prepulse inhibition deficits associated with isolation rearing in female Long-Evans rats. The implication of a central role of nucleus accumbens dopamine in prepulse inhibition deficits in an animal model provides further evidence for a link between overactive dopamine function and sensorimotor-gating deficits in patients with schizophrenia.

5-hydroxytryptamine2A receptor inverse agonists as antipsychotics.

We have used a cell-based functional assay to define the pharmacological profiles of a wide range of central nervous system active compounds as agonists, competitive antagonists, and inverse agonists at almost all known monoaminergic G-protein-coupled receptor (GPCR) subtypes. Detailed profiling of 40 antipsychotics confirmed that as expected, most of these agents are potent competitive antagonists of the dopamine D2 receptor. Surprisingly, this analysis also revealed that most are potent and fully efficacious 5-hydroxytryptamine (5-HT)2A receptor inverse agonists. No other molecular property was shared as universally by this class of compounds. Furthermore, comparisons of receptor potencies revealed that antipsychotics with the highest extrapyramidal side effects (EPS) liability are significantly more potent at D2 receptors, the EPS-sparing atypical agents had relatively higher potencies at 5-HT2A receptors, while three were significantly more potent at 5-HT2A receptors. Functional high-throughput screening of a diverse chemical library identified 530 ligands with inverse agonist activity at 5-HT2A receptors, including several series of compounds related to known antipsychotics, as well as a number of novel chemistries. An analog of one of the novel chemical series, AC-90179, was pharmacologically profiled against the remaining monoaminergic GPCRs and found to be a highly selective 5-HT2A receptor inverse agonist. The behavioral pharmacology of AC-90179 is characteristic of an atypical antipsychotic agent.

Development of spontaneous stereotyped behavior in deer mice: effects of early and late exposure to a more complex environment.

Abnormal repetitive behaviors such as stereotypies are associated with neurodevelopmental disorders and are often observed under conditions of environmental restriction, particularly early in development. Few studies, however, have systematically assessed the effects of environmental enrichment and almost no information is available as to whether a sensitive period exists for such enrichment effects. We hypothesized that spontaneous stereotypies exhibited by deer mice housed under standard laboratory conditions were the result of environmental restriction and that a sensitive period exists for the development/prevention of stereotypies. Exposure to a more complex environment early in the post-weaning period resulted in substantially less stereotypy in the complex environment. Importantly, this outcome was maintained even after mice were housed in standard cages for an identical period of time. Later exposure to the more complex environment also resulted in significantly lower levels of stereotypy compared to controls. These effects were observed in the experimental housing condition as well as in a standard test context. The effects of early and late enrichment support the importance of environmental restriction in the genesis of stereotype and provide support for the efficacy of early and late enrichment in the prevention of stereotypies.

A rodent model of spontaneous stereotypy: initial characterization of developmental, environmental, and neurobiological factors.

Stereotypies are patterns of motor behavior that are repetitive, excessive, topographically invariant, and that lack any obvious function or purpose. In humans, stereotyped behaviors are associated with psychiatric, neurological, and developmental disorders. In animals, stereotypy has been frequently associated with adverse environmental circumstances and often related to alterations in striatal dopamine. To assess the development of stereotyped behaviors and to test the hypothesis that these behaviors are associated with environmental restriction, deer mice were housed in either standard laboratory cages or larger, enriched cages, and the development of stereotypy was followed from weaning over a 17-week period. Standard-caged deer mice engaged in stereotyped behaviors at a higher rate and developed these behaviors more quickly when compared to animals in enriched caging. Additionally, enriched caging was associated with higher rates of patterned running, whereas jumping and backward somersaulting were typically observed in standard cages. In addition, there was a significant effect of litter, but no effect of sex or cage, on the time to develop stereotypy. No differences were found in the density of either striatal D1 or D2 dopamine receptors or the concentration of striatal dopamine or its metabolites as a function of rearing condition or as a function of whether the animals developed stereotypy. These results characterize the development of stereotypies in this species, demonstrate the importance of environmental conditions in the genesis of stereotypy, and suggest that alterations in striatal dopamine content or dopamine receptor density do not account for the expression of stereotyped behaviors in this model.

Self-restraint and self-injury: occurrence and motivational significance.

The occurrence of self-restraint was examined in a sample of 99 adults with severe or profound mental retardation who exhibited self-injury. Results showed that 46% of the sample exhibited self-restraint. A significantly higher occurrence of compulsive behaviors was found for subjects who engaged in self-injury and self-restraint when compared to self-injury subjects without self-restraint. To determine the motivational significance of self-restraint, we assessed the response to brief interruption of this behavior. Subjects who engaged in self-restraint responded more negatively to response interruption than did control subjects. These preliminary findings support the hypothesis that self-injury may be related to a compulsive behavior disorder in some individuals who self-restrain.

Clomipramine treatment for self-injurious behavior of individuals with mental retardation: a double-blind comparison with placebo.

The efficacy of the serotonin (5-HT) uptake inhibitor clomipramine in the treatment of self-injurious behavior (SIB) was tested in individuals with severe and profound mental retardation. Six of the 8 subjects who completed a double-blind, placebo-controlled crossover trial exhibited a clinically significant improvement (50% or greater reduction from placebo) in the frequency of SIB. Clomipramine treatment was also associated with improvement in SIB intensity, frequency of stereotypy and compulsions, teacher ratings of stereotypy and social withdrawal, and frequency of staff intervention required for problem behaviors. Adverse effects (seizure and tachycardia/agitation) occurred in 2 of the 8 subjects. These results represent the first controlled trial of a 5-HT uptake inhibitor in the treatment of SIB in mental retardation.

Growth differences associated with compulsive and stereotyped behavior disorders in adults with mental retardation.

We have recently observed that compulsive behaviors in mentally retarded patients appear to be quite prevalent, can be reliably assessed, and have a high rate of co-occurrence with stereotyped and self-injurious behaviors in this population. As abnormal growth rate has been observed in obsessive-compulsive disorder (OCD) patients, we examined physical stature in adults with mental retardation who display repetitive movement disorders. Identification of cases with stereotypic movement disorder, and cases with compulsive behaviors was done using a symptom checklist and direct observation. Subjects with repetitive movement disorders were smaller in stature than control subjects, with gender differences observed across repetitive behavior disorders. Specifically, female subjects with compulsive behavior disorder, but not stereotypic movement disorder, were significantly shorter and weighted significantly less than same sex-matched controls. Conversely, male subjects with stereotypic movement disorder, but not compulsive disorder, were significantly shorter and weighed significantly less than same sex controls. These findings may point to a neuroendocrine abnormality associated with repetitive movement disorders.

Clomipramine treatment for stereotype and related repetitive movement disorders associated with mental retardation.

The efficacy of the serotonin uptake inhibitor clomipramine in the treatment of stereotyped and related repetitive behavior disorders was tested in individuals with severe and profound mental retardation. A double-blind, placebo-controlled crossover trial of clomipramine was associated with significant reductions in the frequency and intensity of stereotyped behavior and teacher ratings of stereotypy, hyperactivity, and irritability as well as increased adaptive engagement and decreased staff intervention for nontargeted behavior problems. Adverse effects occurred in 3 of the 10 subjects. Of the 7 subjects who tolerated the drug, 6 exhibited a clinically significant improvement in one or more repetitive behaviors. Our results provide support for the hypothesis that clomipramine is effective in treating stereotyped and related behaviors associated with mental retardation.

Compulsions in adults with mental retardation: prevalence, phenomenology, and comorbidity with stereotypy and self-injury.

A variety of conceptual similarities between compulsions seen in individuals with obsessive compulsive disorder and stereotypy and self-injury seen in individuals with mental retardation led us to investigate the prevalence, phenomenology, and comorbidity of compulsions in adults with severe or profound mental retardation. We developed simple assessment screening instruments for stereotypy and self-injury and used Gedye's Compulsive Behavior Checklist and found acceptable levels of reliability, stability, and validity for each instrument. Prevalences were as follows: stereotypy: 60.9%; self-injury: 46.6%; and compulsion: 40%. The occurrence of compulsions was significantly positively associated with the occurrence of stereotypy, self-injury, and stereotypy plus self-injury.

Blink rate as an index of dopamine function in adults with mental retardation and repetitive behavior disorders.

Direct observation of blink rate was used as a noninvasive, in vivo estimate of dopamine function in adults with mental retardation and repetitive behavior disorders. Blink rate as measured in groups of stereotypy, compulsion, and control subjects was highly stable. Subjects with stereotypies had significantly lower blink rates than did control subjects. Although blink rates for compulsive subjects were not significantly different from those of control subjects, a subgroup of compulsive subjects with comorbid stereotypic behaviors displayed significantly lower blink rates. Significant inverse correlations were found for blink rate and severity of repetitive behavior disorder and for blink rate and ratings of motor slowness. These findings support the hypothesis that stereotyped behavior among adults with mental retardation is mediated by hypodopaminergic function.

Automated screening of antenatal samples using a low ionic strength polybrene system.

The use of a two-channel AutoAnalyzer II system in the routine screening of antenatal sera is described. A low ionic strength polybrene method has been used to give optimum detection of IgG antibodies, and hence the system provides a valuable early detection of such antibodies in pregnancy. Of 88 Rhesus antibodies initially detected on the AutoAnalyzer only and followed up later in pregnancy, 18 (20.45%) were later detected by manual methods and were considered to be of potential clinical significance, whilst the remainder were detectable by the AutoAnalyzer only and occurred with a similar frequency as AutoAnalyzer only Rh antibodies in non-immunized males. The sensitivity of the method can provide interpretational difficulties, revealing many apparent "non-specific' reactions as well as detecting low levels of specific antibodies of debatable clinical significance. An approach to dealing with these problems without compromising the benefits of the system is discussed.