Neuromotor and cognitive responses of adults with autism spectrum disorder compared to neurotypical adults.

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder, whose core symptom domains include impaired social communication and narrowed interests and/or repetitive behaviors; in addition, deficits of general cognition, neuromotor function, and movement ability can be observed. This study was designed to examine differences in neuromotor and cognitive functions for a group of young adults with ASD and age-matched controls. It was also of interest to assess whether changes in the intra-individual variability (IIV) of these selected neuromotor and cognitive tasks also occurred. Increased IIV in persons with ASD may reveal important organizational features of their neuromotor system that differ from neurotypical controls. Twenty neurotypical adult individuals (24.3 ± 2.8 years) and twenty adults with a clinician-assigned diagnosis of ASD (21.2 ± 4.4 years) participated in this study. Specific cognitive and motor assessments included Trails Making Tests A&B, Symbol Digit Modalities Test, Purdue Pegboard Test, simple reaction time, finger tapping, hand grip strength, balance, and gait. Results revealed that the ASD adults exhibited decreased upper limb strength and slower responses for finger tapping, hand dexterity, reaction times, and gait compared to the non-ASD controls. The general slowing of motor responses for the persons with ASD was also associated with increased within-subject variability during the reaction time, finger tapping, hand grip, and gait assessments compared to neurotypical adults, illustrating that IIV measures may be a useful marker of widespread neuromotor dysfunction for adults with ASD. Overall, these findings are consistent with clinical observations that abnormalities of movement performance and cognitive performance are an associated feature of ASD in young adults.

A trial of d-cycloserine to treat the social deficit in older adolescents and young adults with autism spectrum disorders.

Autism spectrum disorders are difficult for older adolescents and young adults as impaired social communication affects the transition to adult life. d-Cycloserine, a partial glycine agonist at the N-methyl-d-aspartic acid receptor, was tested in a double-blind randomized trial in 20 older adolescents and young adults with autism spectrum disorders using two dosing strategies (50 mg daily versus 50 mg weekly) for 8 weeks with a 2-week follow-up after discontinuation. d-Cycloserine caused statistically and clinically significant improvement with no differentiation between dosing strategies on the Social Responsiveness Scale and the Aberrant Behavior Checklist before and after d-cycloserine administration.

Clinical outcomes of mild isolated cerebral ventriculomegaly in the presence of other neurodevelopmental risk factors.

OBJECTIVES: The purpose of this study was to evaluate neuropsychological test data in school-aged children whose fetal sonograms revealed mild isolated cerebral ventriculomegaly without asymmetry of the lateral ventricles. METHODS: Nine of 52 children 6 years and older with sonographic evidence of mild isolated cerebral ventriculomegaly without asymmetry of the lateral ventricles were able to be recruited for follow-up school-aged neuropsychological testing. The children received a half-day battery of neuropsychological tests, including the Wechsler Abbreviated Scales of Intelligence; Beery-Buktenica Developmental Test of Visual Motor Integration, Fifth Edition; Wide Range Achievement Test, Fourth Edition; and Integrated Visual and Auditory Continuous Performance Test. Parents completed the Conners 3 Parent Short Form and the Personality Inventory for Children, Second Edition. RESULTS: In this small group, other risk factors for neurodevelopmental disorders were often present, including preterm birth, perinatal hypoxia, and a family history of psychiatric disease or substance abuse. Within this sample, the proportion of children with a pattern of test results showing poorer nonverbal intelligence than verbal intelligence scores and poorer math than reading performance, as well as meeting criteria for a diagnosis of attention deficit/hyperactivity disorder, was higher than the basal rates of these problems among children in general. CONCLUSIONS: Particularly given the complexity of various factors affecting neurodevelopment, follow-up neuropsychological evaluation is warranted in children with sonographic evidence of mild isolated cerebral ventriculomegaly without asymmetry of the lateral ventricle (eg, in the context of poor school performance).

From Mouse to Man: N-Methyl-d-Aspartic Acid Receptor Activation as a Promising Pharmacotherapeutic Strategy for Autism Spectrum Disorders.

The BALB/c mouse displays hypersensitivity to behavioral effects of MK-801 (dizocilpine), a noncompetitive N-methyl-d-aspartic acid (NMDA) receptor "open-channel" blocker, and shows both no preference for an enclosed stimulus mouse over an inanimate object and reduced social interaction with a freely behaving stimulus mouse. NMDA receptor agonist interventions improved measures of social preference and social interaction of the BALB/c mouse model of autism spectrum disorder (ASD). A "proof of principle/proof of concept" translational 10-week clinical trial with 8-week of active medication administration was conducted comparing 20 DSM-IV-TR-diagnosed older adolescent/young adult patients with ASD randomized to once-weekly pulsed administration (50 mg/d) versus daily administration of d-cycloserine (50 mg/d). The results showed that d-cycloserine, a partial glycine agonist, was well tolerated, the 2 dosing strategies did not differ, and improvement was noted on the "lethargy/social withdrawal" and "stereotypic behavior" subscales of the Aberrant Behavior Checklist. NMDA receptor activation contributes to the regulation of mTOR signaling, a pathologic point of convergence in several monogenic syndromic forms of ASD. Furthermore, both NMDA receptor hypofunction and imbalance between NMDA receptor activation mediated by GluN2B and GluN2A-containing NMDA receptors occur as "downstream" consequences of several genetically unrelated abnormalities associated with ASD. NMDA receptor-subtype selective "positive allosteric modulators (PAMs)" are particularly appealing medication candidates for future translational trials.

Targeted NMDA Receptor Interventions for Autism: Developmentally Determined Expression of GluN2B and GluN2A-Containing Receptors and Balanced Allosteric Modulatory Approaches.

Various ASD risk alleles have been associated with impairment of NMDA receptor activation (i.e., NMDA Receptor Hypofunction) and/or disturbance of the careful balance between activation mediated by GluN2B-subtype and GluN2A-subtype-containing NMDA receptors. Importantly, although these various risk alleles affect NMDA receptor activation through different mechanisms, they share the pathogenic consequences of causing disturbance of highly regulated NMDA receptor activation. Disturbances of NMDA receptor activation due to sequence variants, protein termination variants and copy number variants are often cell-specific and regionally selective. Thus, translational therapeutic NMDA receptor agonist interventions, which may require chronic administration, must have specificity, selectivity and facilitate NMDA receptor activation in a manner that is physiologic (i.e., mimicking that of endogenously released glutamate and glycine/D-serine released in response to salient and relevant socio-cognitive provocations within discrete neural circuits). Importantly, knockout mice with absent expression and mice with haploinsufficient expression of the deleterious genes often serve as good models to test the potential efficacy of promising pharmacotherapeutic strategies. The Review considers diverse examples of "illness" genes, their pathogenic effects on NMDA receptor activation and, when available, results of studies of impaired sociability in mouse models, including "proof of principle/proof of concept" experiments exploring NMDA receptor agonist interventions and the development of promising positive allosteric modulators (PAMs), which serve as support and models for developing an inventory of PAMs and negative allosteric modulators (NAMs) for translational therapeutic intervention. Conceivably, selective PAMs and NAMs either alone or in combination will be administered to patients guided by their genotype in order to potentiate and/or restore disrupted balance between activation mediated by GluN2B-subtype and GluN2A-subtype containing NMDA receptors.

Selective mGluR5 antagonism attenuates the stress-induced reduction of MK-801's antiseizure potency in the genetically inbred Balb/c mouse.

The ability of MK-801 (dizocilpine), a noncompetitive N-methyl D-aspartate (NMDA) antagonist, to antagonize electrical seizures is reduced in stressed mice. Stress-associated alterations in seizure susceptibility and diminished efficacy of antiseizure medications in humans have been reported [Joëls, 2009; Haut et al., 2007; Moshe et al., 2008]; thus, these experimental observations implicate altered endogenous tone of NMDA receptor-mediated neurotransmission in clinically adverse effects of stress on seizure proneness and treatment. The current exploratory experiment examined the effect of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), an antagonist of mGluR5, administered prior to stress on the stress-induced reduction of MK-801's antiseizure effect in Swiss-Webster and Balb/c mice; the Balb/c mouse is behaviorally hypersensitive to MK-801. Interestingly, the data suggest that MPEP can attenuate the severity of the stress-induced reduction of MK-801's antiseizure effect in the Balb/c strain. Thus, mGluR5 could serve as a target for strategies for adjuvant treatment of seizures exacerbated by stress.

Psychotropic medication use for adults and older adults with intellectual disability; selective review, recommendations and future directions.

A growing expert consensus has emerged to guide prescribing behavior and monitoring of psychotropic medications in adults and older adults with intellectual disability (ID). However, there is little empirically-derived evidence to inform physician selection of specific categories of psychotropic medication for treatment of "challenging" behaviors in this vulnerable population (such as aggression to self, others and objects; self-injurious behaviors; repetitive stereotypic behaviors; and hyperactivity). Difficulties with application of formal definitional diagnostic criteria and reliable assignment of psychiatric diagnoses to adults with ID, which is often difficult due to their poor communication skills, contribute to confusion and uncertainty surrounding medication selection. Long-term administration of antipsychotic medications are commonly prescribed for challenging behaviors in spite of their questionable long-term efficacy, leading some to suggest that their "episodic" short-term administration for imminent dangerousness to self and others or when difficult-to-find residential placements are threatened is preferred to their long-term administration. Further, literature supports engagement of interdisciplinary treatment teams to seek causes for challenging behaviors, formulate non-pharmacological psychosocial and behavioral plans for their amelioration and, if medications are initiated, convene regular medication monitoring to identify "drug-related problems". Medication monitoring is important because medication-related adverse events cause or contribute to challenging behaviors, which can sometimes be improved by dose reduction, medication discontinuation and/or elimination of polypharmacy and co-pharmacy. Importantly, medications themselves may interfere with self-reported measures of Quality of Life. The data clearly highlight the need for well-designed randomized controlled clinical trials in samples that are homogeneous with respect to severity of ID and residential setting; moreover, they should include a wider variety of clinical and safety outcome measures. Preclinical studies have suggested novel pharmacological strategies to prevent progressive worsening of adaptive function in adults with Down syndrome in particular, and improvement of cognition in adults with ID in general, irrespective of the etiopathogenesis of the ID. Translational clinical trials to address pathogenic mechanisms of ID, as well as challenging behaviors, are anticipated but raise societal issues pertaining to protection of this vulnerable population enrolling in clinical trials and prioritization of urgent therapeutic targets (e.g., amelioration of challenging behaviors versus improving or preserving intellectual functioning).

A De Novo Missense Variant of SCN2A: Implications and Limitations for Understanding Clinical Phenotype and Treatment Recommendations.

ABSTRACT: Autism spectrum disorder can be associated with a variety of genetic findings. We report a heterozygous de novo missense variant of SCN2A, the gene coding a voltage-gated sodium ion channel enriched in the axon initial segment and nodes of Ranvier of "immature" neocortical pyramidal neurons. With further understanding of the neurodevelopmental and functional effects of this missense variant on neuronal excitability and neocortical circuitry, there may be targeted pharmacotherapeutic interventions, potentially with "disease-modifying effects."

Perineuronal Nets and Metal Cation Concentrations in the Microenvironments of Fast-Spiking, Parvalbumin-Expressing GABAergic Interneurons: Relevance to Neurodevelopment and Neurodevelopmental Disorders.

Because of their abilities to catalyze generation of toxic free radical species, free concentrations of the redox reactive metals iron and copper are highly regulated. Importantly, desired neurobiological effects of these redox reactive metal cations occur within very narrow ranges of their local concentrations. For example, synaptic release of free copper acts locally to modulate NMDA receptor-mediated neurotransmission. Moreover, within the developing brain, iron is critical to hippocampal maturation and the differentiation of parvalbumin-expressing neurons, whose soma and dendrites are surrounded by perineuronal nets (PNNs). The PNNs are a specialized component of brain extracellular matrix, whose polyanionic character supports the fast-spiking electrophysiological properties of these parvalbumin-expressing GABAergic interneurons. In addition to binding cations and creation of the Donnan equilibrium that support the fast-spiking properties of this subset of interneurons, the complex architecture of PNNs also binds metal cations, which may serve a protective function against oxidative damage, especially of these fast-spiking neurons. Data suggest that pathological disturbance of the population of fast-spiking, parvalbumin-expressing GABAergic inhibitory interneurons occur in at least some clinical presentations, which leads to disruption of the synchronous oscillatory output of assemblies of pyramidal neurons. Increased expression of the GluN2A NMDA receptor subunit on parvalbumin-expressing interneurons is linked to functional maturation of both these neurons and the perineuronal nets that surround them. Disruption of GluN2A expression shows increased susceptibility to oxidative stress, reflected in redox dysregulation and delayed maturation of PNNs. This may be especially relevant to neurodevelopmental disorders, including autism spectrum disorder. Conceivably, binding of metal redox reactive cations by the perineuronal net helps to maintain safe local concentrations, and also serves as a reservoir buffering against second-to-second fluctuations in their concentrations outside of a narrow physiological range.

An Evolving Therapeutic Rationale for Targeting the α7 Nicotinic Acetylcholine Receptor in Autism Spectrum Disorder.

Abnormalities of cholinergic nuclei, cholinergic projections, and cholinergic receptors, as well as abnormalities of growth factors involved in the maturation and maintenance of cholinergic neurons, have been described in postmortem brains of persons with autism spectrum disorder (ASD). Further, microdeletions of the 15q13.3 locus that encompasses CHRNA7, the gene coding the α7 nicotinic acetylcholine receptor (α7 nAChR), are associated with a spectrum of neurodevelopmental disorders, including ASD. The heterozygous 15q13.3 microdeletion syndrome suggests that diminished or impaired transduction of the acetylcholine (ACh) signal by the α7 nAChR can be a pathogenic mechanism of ASD. The α7 nAChR has a role in regulating the firing and function of parvalbumin (PV)-expressing GABAergic projections, which synchronize the oscillatory output of assemblies of pyramidal neurons onto which they project. Synchronous oscillatory output is an electrophysiological substrate for higher executive functions, such as working memory, and functional connectivity between discrete anatomic areas of the brain. The α7 nAChR regulates PV expression and works cooperatively with the co-expressed NMDA receptor in subpopulations of GABAergic interneurons in mouse models of ASD. An evolving literature supports therapeutic exploration of selectively targeted cholinergic interventions for the treatment of ASD, especially compounds that target the α7 nAChR subtype. Importantly, development and availability of high-affinity, brain-penetrable, α7 nAChR-selective agonists, partial agonists, allosteric agonists, and positive allosteric modulators (PAMs) should facilitate "proof-of-principle/concept" clinical trials. nAChRs are pentameric allosteric proteins that function as ligand-gated ion channel receptors constructed from five constituent polypeptide subunits, all of which share a common structural motif. Importantly, in addition to α7 nAChR-gated Ca2+ conductance causing membrane depolarization, there are emerging data consistent with possible metabotropic functions of this ionotropic receptor. The ability of α7-selective type II PAMs to "destabilize" the desensitized state and promote ion channel opening may afford them therapeutic advantages over orthosteric agonists. The current chapter reviews historic and recent literature supporting selective therapeutic targeting of the α7 nAChR in persons affected with ASD.

Glycine transporter type 1 (GlyT1) inhibition improves conspecific-provoked immobility in BALB/c mice: Analysis of corticosterone response and glucocorticoid gene expression in cortex and hippocampus.

Stress reactivity and glucocorticoid signaling alterations are reported in mouse models of autism spectrum disorder (ASD). BALB/c mice display decreased locomotor activity in the presence of stimulus mice and spend less time exploring enclosed stimulus mice; this mouse strain has been validated as an ASD model. VU0410120, a glycine type 1 transporter (GlyT1) inhibitor, improved sociability in BALB/c mice, consistent with data that NMDA Receptor (NMDAR) activation regulates sociability, and the endogenous tone of NMDAR-mediated neurotransmission is altered in this strain. Effects of a prosocial dose of VU0410120 on conspecific-provoked immobility, and relationships between conspecific-provoked immobility and corticosterone response were explored. VU0410120-treated BALB/c mice showed reduced immobility in the presence of conspecifics and increased the conspecific-provoked corticosterone response. However, the intensity of conspecific-provoked immobility in VU0410120-treated BALB/c mice did not differ as a function of corticosterone response. Expression profiles of 88 glucocorticoid signaling associated genes within frontal cortex and hippocampus were examined. BALB/c mice resistant to prosocial effects of VU0410120 had increased mRNA expression of Ddit4, a negative regulator of mTOR signaling. Dysregulated mTOR signaling activity is a convergent finding in several monogenic syndromic forms of ASD. Prosocial effects of VU0410120 in the BALB/c strain may be related to regulatory influences of NMDAR-activation on mTOR signaling activity. Because corticosterone response is a marker of social stress, the current data suggest that the stressfulness of a social encounter alone may not be the sole determinant of increased immobility in BALB/c mice; this strain may also display an element of social disinterest.

Genetically inbred Balb/C mice are more sensitive to an effect of flurazepam and more resistant to an effect of stress than a genetically outbred mouse strain.

The inbred Balb/c mouse strain was more sensitive than the outbred NIH Swiss mouse to flurazepam's ability to antagonize electrically precipitated seizures. In prior work, a reduction in flurazepam's antiseizure efficacy was not observed 24h after forcing Balb/c mice to swim for up to 10 min in ambient temperature water. Thus, we wondered if a stress-induced reduction would be observed after forcing mice to swim for up to 10 min in cold (6 degrees C) water, a more severe stress. The current data show that 24 h after exposure to this stress, the ability of flurazepam to raise the threshold voltage for the elicitation of tonic hindlimb extension in the Balb/c mouse strain was reduced. The genetically inbred Balb/c mouse strain is emerging as an interesting animal model in which to study interactions of stress and genetic factors that affect endogenous neurotransmission mediated by l-glutamate and GABA at the NMDA and GABA(A) receptor complexes, respectively.

Recognition memory probes affect what is remembered in schizophrenia.

Cognitive psychology offers tools to localize the memory processes most vulnerable to disruption in schizophrenia and to identify how patients with schizophrenia best remember. In this research, we used the University of Southern California Repeatable Episodic Memory Test (USC-REMT; Parker, E.S., Landau, S.M., Whipple, S.C., Schwartz, B.L., 2004. Aging, recall, and recognition: A study on the sensitivity of the University of Southern California Repeatable Episodic Memory Test (USC-REMT). Journal of Clinical and Experimental Neuropsychology 26(3), 428-440.) to examine how two different recognition memory probes affect memory performance in patients with schizophrenia and matched controls. Patients with schizophrenia studied equivalent word lists and were tested by yes-no recognition and forced-choice recognition following identical encoding and storage conditions. Compared with controls, patients with schizophrenia were particularly impaired when tested by yes-no recognition relative to forced-choice recognition. Patients had greatest deficits on hits in yes-no recognition but did not exhibit elevated false alarms. The data point to the importance of retrieval processes in schizophrenia, and highlight the need for further research on ways to help patients with schizophrenia access what they have learned.

Understanding facial expressivity in autism spectrum disorder: An inside out review of the biological basis and clinical implications.

Deficits in decoding and understanding facially expressed emotions occur commonly in persons with autism spectrum disorder (ASD), which contribute to the impairment of social communication that serves as one of its core diagnostic criteria. Research suggests that abnormalities of visual scanning of the face, activation of key nodes within the "social brain" by facially expressed emotions, functional connectivity within and between nodes of the "social brain", and transduction of specific neurotransmitter/neuromodulatory signals contribute to the pathogenesis of these deficits in at least some persons with ASD. Importantly, the etiologies of these deficits are heterogeneous and include genetic, immunologic, and inflammatory mechanisms, as well as in utero exposures to drugs and toxins. The manifestation and severity of these deficits can also be influenced by developmental age, IQ and genetic background. Consistent with the goals of the Special Issue, the current Review is intended to familiarize the readership with several of the leading neurobiological mechanisms proposed to underlie these deficits in decoding facially expressed emotions and stimulate interest in translational preclinical and clinical investigations, whose ultimate purpose is to attenuate their severity and, thereby, improve functional outcomes of persons with ASD.

Metabotropic functions of the NMDA receptor and an evolving rationale for exploring NR2A-selective positive allosteric modulators for the treatment of autism spectrum disorder.

NMDA receptors are widely distributed throughout the brain and major therapeutic challenges include targeting specific NMDA receptor subtypes while preserving spatial and temporal specificity during their activation. The NR2A-subunit containing NMDA receptor is implicated in regulating synchronous oscillatory output of cortical pyramidal neurons, which may be disturbed in clinical presentations of autism spectrum disorder (ASD). Because NR2A-selective positive allosteric modulators (PAMs) preserve spatial and temporal selectivity while activating this subpopulation of receptors, they represent a promising strategy to address neocortical circuit abnormalities in ASD. In addition to promoting Ca2+ entry and membrane depolarization, diverse metabotropic effects of NMDA receptor activation on signal transduction pathways occur within the cell, some of which depend on alignment of protein binding partners. For example, NMDA receptor agonist interventions attenuate impaired sociability in transgenic mice with 'loss-of-function' mutations of the Shank family of scaffolding proteins, which highlights the necessity of a carefully orchestrated alignment of protein binding partners in the excitatory synapse. The current Review considers metabotropic functions of the NMDA receptor that could play a role in sociability and the pathogenesis of ASD (e.g., mTOR signaling), in addition to its more familiar ionotropic functions, and provides a rationale for therapeutic exploration of NR2A-selective PAMs.

Sexuality in the Autism Spectrum Study (SASS): Reports from Young Adults and Parents.

Previous research indicates that although those with ASD desire sexual relationships, they may not effectively engage in romantic and intimate interactions. The purpose of this study was to compare reports from young adults with ASD and parents from the same families on the young adult's sexual behavior, experiences, knowledge, and communication. 100 young adults (18-30 years) and parents completed an online survey. Results indicated that young adults reported more typical privacy and sexual behaviors, and higher sexual victimization than their parents reported on their behalf. Our findings indicated that individuals with ASD desire and pursue sexual relationships typical of most people and suggest the need for sex education and communication about topics generally covered for neurotypically developing young adults.

Sodium butyrate, an epigenetic interventional strategy, attenuates a stress-induced alteration of MK-801's pharmacologic action.

Twenty-four hours after mice are exposed to a single session of forced swimming in cold water, the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist, to antagonize electrically precipitated seizures is reduced. Conceivably, this reduction in MK-801's antiseizure efficacy reflects a stress-induced alteration in NMDA receptor-mediated neurotransmission due to changes in gene expression 24 h after a single stress. Recently, epigenetic interventional strategies impacting expression of genes whose regulation is controlled by the acetylation status of histone proteins in the nucleosome, an octomeric complex of histone proteins and promoter regions of double-stranded DNA, have been tested in preclinical models of various neuropsychiatric disorders, including Huntington disease and major depression. These strategies have been studied extensively in cancer biology. In the current investigation, the severity of the stress-induced reduction of MK-801's ability to raise the threshold voltage for the elicitation of tonic hindlimb extension was reduced when sodium butyrate (1.5 g/kg, ip) was administered around the time of stress. Prior research showed that this dose of sodium butyrate reliably increased the acetylation status of H3 and H4 histone proteins in the hippocampus and cerebral cortex of mice. Thus, the attenuation of the stress-induced reduction of MK-801's antiseizure efficacy may be due to the increased acetylation of histone proteins in the nucleosomal core and promotion of gene expression. These data encourage development of epigenetic strategies to prevent some of the deleterious consequences of stress.

Expression of NR1, NR2A and NR2B NMDA receptor subunits is not altered in the genetically-inbred Balb/c mouse strain with heightened behavioral sensitivity to MK-801, a noncompetitive NMDA receptor antagonist.

The genetically-inbred Balb/c mouse strain shows heightened sensitivity to the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist, to raise the threshold voltage necessary to precipitate tonic hindlimb extension and elicit irregular episodes of intense jumping behavior (referred to as "popping"), relative to other inbred mouse strains and the outbred NIH Swiss mouse. Moreover, an allosteric modulatory effect of sarcosine, a glycine reuptake inhibitor, on MK-801's antagonism of electrically precipitated seizures was detected 24 h after Balb/c mice were forced to swim in cold water for up to 10 min; this was not observed in unstressed Balb/c mice or stressed or unstressed NIH Swiss mice. Phencyclidine (PCP), a noncompetitive NMDA receptor antagonist that binds to the same hydrophobic channel domain as MK-801, precipitates a schizophreniform psychosis in susceptible individuals that shares descriptive similarities with schizophrenia. This observation has led to the hypothesis that NMDA receptor hypofunction (NRH) is involved in the pathophysiology of schizophrenia and the testing of pharmacotherapeutic strategies to facilitate NMDA receptor-mediated neurotransmission in patients with this disorder (e.g., glycine reuptake inhibitors). The heightened behavioral sensitivity of the Balb/c mouse to MK-801 suggests that this mouse strain may be a useful model to study "psychosis-proneness" and screen for positive allosteric modulators of NMDA receptor-mediated neurotransmission. Conceivably, strain differences in the pharmacology of the NMDA receptor are due to differences in the relative expression of individual NMDA receptor subunits to each other (i.e., combinatorial regulation). The current study compared the normal protein expression patterns of six of the eight identified splice variant isoforms of the NR1 NMDA receptor subunit, and NR2A and NR2B subunits in the hippocampus and cerebral cortex of Balb/c and NIH Swiss mice. The heightened behavioral sensitivity of the Balb/c genetically-inbred mouse strain to MK-801, compared to the outbred NIH Swiss mouse strain, does not appear to result from relative alterations of expression of these NMDA receptor protein subunits that were examined.

Guanosine possesses specific modulatory effects on NMDA receptor-mediated neurotransmission in intact mice.

Guanosine, a purine nucleotide, promotes the reuptake of l-glutamate by astrocytes; astrocytic reuptake of glutamate is a major mechanism of its synaptic inactivation. The current experiments showed that guanosine reduced the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor "open-channel" blocker, to raise the threshold voltage for electrically-precipitated tonic hindlimb extension in unstressed intact mice. This modulatory effect may be due to guanosine's removal of glutamate from the synaptic cleft, resulting in a reduced proportion of NMDA receptor-associated ion channels in the open configuration. The modulatory effect of guanosine on MK-801's ability to disrupt rotorod performance in unstressed mice or antagonize electrically-precipitated seizures in stressed mice was not seen. The inability to demonstrate modulation in the rotorod paradigm may reflect the sensitivity of this measure of motor incoordination to MK-801's disruptive effects. Whereas failure to see this effect in our incremental electroconvulsive shock paradigm in stressed mice may be due to the fact that stress and guanosine act in the same direction to reduce MK-801's antiseizure efficacy. Given the phencyclidine model of schizophrenia and its pharmacological actions as a noncompetitive NMDA receptor "open-channel" blocker and guanosine's antagonistic effect on MK-801's antiseizure efficacy in unstressed mice, the current data support development of guanine-based purines for the treatment of at least some aspects of schizophrenia.

Effects of CDP-choline and the combination of CDP-choline and galantamine differ in an animal model of schizophrenia: development of a selective alpha7 nicotinic acetylcholine receptor agonist strategy.

The regionally selective reduction of expression of the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) in schizophrenia underlies impaired sensory inhibition, a possible endophenotype of the disorder. This ligand-gated ion channel receptor has been proposed as a pharmacotherapeutic target in schizophrenia. The current study examined the effect of CDP-choline alone and the combination of CDP-choline and galantamine, administered acutely and once-daily for five consecutive days, in an animal model of NMDA receptor hypofunction that is relevant to schizophrenia. The results support the allosteric modulatory influence of galantamine on CDP-choline; however, individual doses of CDP-choline and galantamine must be carefully titrated in order to achieve optimal levels of alpha7 nAChR "agonism" that may be necessary for the desired therapeutic effect.