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.

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.

Exposure to Low (≤10 cGy) Doses of 4He Particles Leads to Increased Social Withdrawal and Loss of Executive Function Performance.

Astronauts on the planned mission to Mars will be exposed to galactic cosmic radiation (GCR), with proton and He particles accounting (in approximately equal amounts) for ∼75% of the equivalent dose. Exposure to ≤15 cGy of space radiation ions with Z ≥ 15 particles has been shown to impair various executive functions, including attentional set shifting and creative problem-solving in rats. Executive functions also regulate social interactions and mood. Should space radiation exposure alter these executive functions as it does cognitive flexibility, there is the possibility of altered interactions among crew members and team cooperativity during prolonged space exploration. This study characterized the effects of ≤10 cGy 400 MeV/n of 4He particles on cognitive flexibility and social interaction (within freely interacting dyads) in male Wistar rats. Exposure to ≥1 cGy 4He ions induced deficits in the SD and/or CD stages of the attentional set shifting (ATSET) task, as reported after exposure to Z ≥ 15 space radiation ions. Should similar effects occur in astronauts, these data suggest that they would have a reduced ability to identify key events in a new situation and would be more easily distracted by extraneous variables. The irradiated rats were also screened for performance in a task for unconstrained cognitive flexibility (UCFlex), often referred to as creative problem-solving. There was a marked dose-dependent change in UCFlex performance with ∼30% of rats exposed to 10 cGy being unable to solve the problem, while the remaining rats took longer than the sham-irradiated animals to resolve the problem. Importantly, performance in the ATSET test was not indicative of UCFlex performance. From a risk assessment perspective, these findings suggest that a value based on a single behavioral end point may not fully represent the cognitive deficits induced by space radiation, even within the cognitive flexibility domain. Rats that received 5 cGy 4He ion irradiation had a significantly lower level of interaction toward their sham-irradiated partners in a non-anxiogenic (uncaged) dyad interactions study. This is consistent with the social withdrawal previously observed in space radiation-exposed male mice in a three-chamber test. 4He-irradiated rats exhibited a significantly higher incidence and duration of self-grooming, which is even more concerning, given that their dyad partners were able to physically interact with the irradiated rats (i.e., touching/climbing over them). This study has established that exposure of male rats to "light" ions such as He affects multiple executive functions resulting in deficits in both sociability and cognitive flexibility, and possibly affective behavior (reward valuation). Further studies are needed to determine if these space radiation-induced co-morbidities are concomitantly induced within individual rats.

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."

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).

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.

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.

Sugarcoated Perineuronal Nets Regulate "GABAergic" Transmission: Bittersweet Hypothesis in Autism Spectrum Disorder.

Fast-spiking, parvalbumin-expressing "GABAergic" interneurons regulate synchronous oscillatory output of pyramidal neurons. Metabolic demands of these GABAergic projections are great because local ion concentrations must be optimally maintained; in addition, high rates of mitochondrial respiration necessitate exquisite redox regulation. Interestingly, only fast-spiking, parvalbumin-expressing basket cells coexpressing 3 metalloproteinases seem to be preferentially enwrapped in perineuronal nets (PNNs), a specialized lattice-like structure of the extracellular matrix. The PNNs maintain optimal local concentrations of ions, protect against oxidative stress, and concentrate transcription factors and chemorepulsive axon guidance cues. The PNNs mediate opening and closing of periods of heightened plasticity. Therapeutic strategies in autism spectrum disorders include promoting both maintenance and deliberate disruption of PNNs to promote new learning and cognitive flexibility.

Age-dependent effects on social interaction of NMDA GluN2A receptor subtype-selective antagonism.

NMDA receptor-mediated neurotransmission is implicated in the regulation of normal sociability in mice. The heterotetrameric NMDA receptor is composed of two obligatory GluN1 and either two "modulatory" GluN2A or GluN2B receptor subunits. GluN2A and GluN2B-containing receptors differ in terms of their developmental expression, distribution between synaptic and extrasynaptic locations, and channel kinetic properties, among other differences. Because age-dependent differences in disruptive effects of GluN2A and GluN2B subtype-selective antagonists on sociability and locomotor activity have been reported in rats, the current investigation explored age-dependent effects of PEAQX, a GluN2A subtype-selective antagonist, on sociability, stereotypic behaviors emerging during social interaction, and spatial working memory in 4- and 8-week old male Swiss Webster mice. The data implicate an age-dependent contribution of GluN2A-containing NMDA receptors to the regulation of normal social interaction in mice. Specifically, at a dose of PEAQX devoid of any effect on locomotor activity and mouse rotarod performance, the social interaction of 8-week old mice was disrupted without any effect on the social salience of a stimulus mouse. Moreover, PEAQX attenuated stereotypic behavior emerging during social interaction in 4- and 8-week old mice. However, PEAQX had no effect on spontaneous alternations, a measure of spatial working memory, suggesting that neural circuits mediating sociability and spatial working memory may be discrete and dissociable from each other. Also, the data suggest that the regulation of stereotypic behaviors and sociability may occur independently of each other. Because expression of GluN2A-containing NMDA receptors occurs at a later developmental stage, they may be more involved in mediating the pathogenesis of ASDs in patients with histories of "regression" after a period of normal development than GluN2B receptors.

Experimental Assessment of Mouse Sociability Using an Automated Image Processing Approach.

Mouse is the preferred model organism for testing drugs designed to increase sociability. We present a method to quantify mouse sociability in which the test mouse is placed in a standardized apparatus and relevant behaviors are assessed in three different sessions (called session I, II, and III). The apparatus has three compartments (see Figure 1), the left and right compartments contain an inverted cup which can house a mouse (called "stimulus mouse"). In session I, the test mouse is placed in the cage and its mobility is characterized by the number of transitions made between compartments. In session II, a stimulus mouse is placed under one of the inverted cups and the sociability of the test mouse is quantified by the amounts of time it spends near the cup containing the enclosed stimulus mouse vs. the empty inverted cup. In session III, the inverted cups are removed and both mice interact freely. The sociability of the test mouse in session III is quantified by the number of social approaches it makes toward the stimulus mouse and by the number of times it avoids a social approach by the stimulus mouse. The automated evaluation of the movie detects the nose of the test mouse, which allows the determination of all described sociability measures in session I and II (in session III, approaches are identified automatically but classified manually). To find the nose, the image of an empty cage is digitally subtracted from each frame of the movie and the resulting image is binarized to identify the mouse pixels. The mouse tail is automatically removed and the two most distant points of the remaining mouse are determined; these are close to nose and base of tail. By analyzing the motion of the mouse and using continuity arguments, the nose is identified. Figure 1. Assessment of Sociability During 3 sessions. Session I (top): Acclimation of test mouse to the cage. Session II (middle): Test mouse moving freely in the cage while the stimulus mouse is enclosed in an inverted cup. Session III (bottom): Both test mouse and stimulus mouse are allowed to move freely and interact with each other.

Characterization of gait and olfactory behaviors in the Balb/c mouse model of autism spectrum disorders.

Abnormalities of gait and olfaction have been reported in persons with autism spectrum disorders (ASDs), which could reflect involvement of the cerebellum and nodes related to olfaction (e.g., olfactory bulb and ventral temporal olfactory cortex) in neural circuits subserving social, cognitive, and motor domains of psychopathology in these disorders. We hypothesized that the Balb/c mouse model of ASD would express "abnormalities" of gait and olfaction, relative to the Swiss Webster comparator strain. Contrary to expectation, Balb/c and Swiss Webster mice did not differ in terms of quantitative measurements of gait and mouse rotarod behavior, and Balb/c mice displayed a shorter latency to approach an unscented cotton swab, suggesting that there was no disturbance of its locomotor behavior. However, Balb/c mice showed significant inhibition of locomotor activity in the presence of floral scents, including novel and familiar floral scents, and a socially salient odor (i.e., concentrated mouse urine); the inhibitory effect on the locomotor behavior of the Balb/c mouse was especially pronounced with the salient social odor. Unlike the Swiss Webster strain, mouse urine lacks social salience for the Balb/c mouse strain, a model of ASD, which does not appear to be an artifact of diminished olfactory sensitivity or impaired locomotion.

The 15q13.3 deletion syndrome: Deficient α(7)-containing nicotinic acetylcholine receptor-mediated neurotransmission in the pathogenesis of neurodevelopmental disorders.

Array comparative genomic hybridization (array CGH) has led to the identification of microdeletions of the proximal region of chromosome 15q between breakpoints (BP) 3 or BP4 and BP5 encompassing CHRNA7, the gene encoding the α7-nicotinic acetylcholine receptor (α7nAChR) subunit. Phenotypic manifestations of persons with these microdeletions are variable and some heterozygous carriers are seemingly unaffected, consistent with their variable expressivity and incomplete penetrance. Nonetheless, the 15q13.3 deletion syndrome is associated with several neuropsychiatric disorders, including idiopathic generalized epilepsy, intellectual disability, autism spectrum disorders (ASDs) and schizophrenia. Haploinsufficient expression of CHRNA7 in this syndrome has highlighted important roles the α7nAChR plays in the developing brain and normal processes of attention, cognition, memory and behavior throughout life. Importantly, the existence of the 15q13.3 deletion syndrome contributes to an emerging literature supporting clinical trials therapeutically targeting the α7nAChR in disorders such as ASDs and schizophrenia, including the larger population of patients with no evidence of haploinsufficient expression of CHRNA7. Translational clinical trials will be facilitated by the existence of positive allosteric modulators (PAMs) of the α7nAChR that act at sites on the receptor distinct from the orthosteric site that binds acetylcholine and choline, the receptor's endogenous ligands. PAMs lack intrinsic efficacy by themselves, but act where and when the endogenous ligands are released in response to relevant social and cognitive provocations to increase the likelihood they will result in α7nAChR ion channel activation.

The α7 nicotinic acetylcholine receptor: A mediator of pathogenesis and therapeutic target in autism spectrum disorders and Down syndrome.

Currently, there are no medications that target core deficits of social communication and restrictive, repetitive patterns of behavior in persons with autism spectrum disorders (ASDs). Adults with Down syndrome (DS) display a progressive worsening of adaptive functioning, which is associated with Alzheimer's disease (AD)-like histopathological changes in brain. Similar to persons with ASDs, there are no effective medication strategies to prevent or retard the progressive worsening of adaptive functions in adults with DS. Data suggest that the α7-subunit containing nicotinic acetylcholine receptor (α7nAChR) is implicated in the pathophysiology and serves as a promising therapeutic target of these disorders. In DS, production of the amyloidogenic Aß1-42 peptide is increased and binds to the α7nAChR or the lipid milieu associated with this receptor, causing a cascade that results in cytotoxicity and deposition of amyloid plaques. Independently of their ability to inhibit the complexing of Aß1-42 with the α7nAChR, α7nAChR agonists and positive allosteric modulators (PAMs) also possess procognitive and neuroprotective effects in relevant in vivo and in vitro models. The procognitive and neuroprotective effects of α7nAChR agonist interventions may be due, at least in part, to stimulation of the PI3K/Akt signaling cascade, cross-talk with the Wnt/ß-catenin signaling cascade and both transcriptional and non-transcriptional effects of ß-catenin, and effects of transiently increased intraneuronal concentrations of Ca(2+) on metabolism and the membrane potential. Importantly, α7nAChR PAMs are particularly attractive medication candidates because they lack intrinsic efficacy and act only when and where endogenous acetylcholine is released or choline is generated.

Effects of VU0410120, a novel GlyT1 inhibitor, on measures of sociability, cognition and stereotypic behaviors in a mouse model of autism.

The NMDA receptor is a highly regulated glutamate-gated cationic channel receptor that has an important role in the regulation of sociability and cognition. The genetically-inbred Balb/c mouse has altered endogenous tone of NMDA receptor-mediated neurotransmission and is a model of impaired sociability, relevant to Autism Spectrum Disorders (ASDs). Because glycine is an obligatory co-agonist that works cooperatively with glutamate to promote opening of the ion channel, one prominent strategy to promote NMDA receptor-mediated neurotransmission involves inhibition of the glycine type 1 transporter (GlyT1). The current study evaluated the dose-dependent effects of VU0410120, a selective, high-affinity competitive GlyT1 inhibitor, on measures of sociability, cognition and stereotypic behaviors in Balb/c and Swiss Webster mice. The data show that doses of VU0410120 (i.e., 18 and 30mg/kg) that improve measures of sociability and spatial working memory in the Balb/c mouse strain elicit intense stereotypic behaviors in the Swiss Webster comparator strain (i.e., burrowing and jumping). Furthermore, the data suggest that selective GlyT1 inhibition improves sociability and spatial working memory at doses that do not worsen or elicit stereotypic behaviors in a social situation in the Balb/c strain. However, the elicitation of stereotypic behaviors in the Swiss Webster comparator strain at therapeutically relevant doses of VU0410120 suggest that genetic factors (i.e., mouse strain differences) influence sensitivity to GlyT1-elicited stereotypic behaviors, and emergence of intense stereotypic behaviors may be dose-limiting side effects of this interventional strategy.

NMDA receptor activation regulates sociability by its effect on mTOR signaling activity.

Tuberous Sclerosis Complex is one example of a syndromic form of autism spectrum disorder associated with disinhibited activity of mTORC1 in neurons (e.g., cerebellar Purkinje cells). mTORC1 is a complex protein possessing serine/threonine kinase activity and a key downstream molecule in a signaling cascade beginning at the cell surface with the transduction of neurotransmitters (e.g., glutamate and acetylcholine) and nerve growth factors (e.g., Brain-Derived Neurotrophic Factor). Interestingly, the severity of the intellectual disability in Tuberous Sclerosis Complex may relate more to this metabolic disturbance (i.e., overactivity of mTOR signaling) than the density of cortical tubers. Several recent reports showed that rapamycin, an inhibitor of mTORC1, improved sociability and other symptoms in mouse models of Tuberous Sclerosis Complex and autism spectrum disorder, consistent with mTORC1 overactivity playing an important pathogenic role. NMDA receptor activation may also dampen mTORC1 activity by at least two possible mechanisms: regulating intraneuronal accumulation of arginine and the phosphorylation status of a specific extracellular signal regulating kinase (i.e., ERK1/2), both of which are "drivers" of mTORC1 activity. Conceivably, the prosocial effects of targeting the NMDA receptor with agonists in mouse models of autism spectrum disorders result from their ability to dampen mTORC1 activity in neurons. Strategies for dampening mTORC1 overactivity by NMDA receptor activation may be preferred to its direct inhibition in chronic neurodevelopmental disorders, such as autism spectrum disorders.

Targeting the α7 nicotinic acetylcholine receptor to prevent progressive dementia and improve cognition in adults with Down's syndrome.

As persons with Down's syndrome (DS) age into the third decade and beyond, they develop Alzheimer's disease (AD)-like histopathological changes in brain and may manifest progressive worsening of adaptive functions. Increasingly, persons with DS have near-normal to normal life spans; thus, it has become a therapeutic imperative to preserve adaptive functions and ability to live as independently as possible in the least restrictive environment throughout adulthood. Data suggest that these histopathological changes and worsening adaptive functions result, at least in part, from the binding of the amyloidogenic Aß1-42 peptide to α7 nicotinic acetylcholine receptors (α7nAChRs) on the surface of neurons, which can lead to the internalization of the tightly-bound complex and cell lysis. Pharmacotherapeutic targeting of the α7nAChR may inhibit the creation of the Aß1-42-α7nAChR complex, which has been observed both intraneuronally and as a component of the amyloid plaque seen in AD. Additionally, selective α7nAChR agonists may improve memory and cognition independently of their potential ability to attenuate the cytotoxicity of Aß1-42 and retard the deposition of amyloid plaques in adults with DS. However, there are conflicting data supporting an antagonist strategy to improve cognition in the presence of elevated levels of Aß amyloidogenic peptides, as well as to prevent emergence of pyramidal neuron hyperexcitability. A major challenge to the implementation of clinical trials of targeted α7nAChR interventions in adults with DS will be the ability to detect medication-induced changes in cognition in the context of intellectual disability. The Review will consider some of the current evidence supporting both the role of the Aß1-42-α7nAChR complex in the pathogenesis of the AD-like histopathology in adult persons with DS, and pharmacotherapeutic interventions with α7nAChR agonists.

NMDA receptors on the surface of cancer cells: target for chemotherapy?

The mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a therapeutic target for many types of cancers. NMDA receptors regulate mTOR signalling activity; their inappropriate expression on several human cancer cell lines represents a potential therapeutic avenue to control dysregulated growth, division and invasiveness. Targeting these receptors with selective ligands (e.g., glycineB site ligands) may be a less toxic and more tolerable approach than administering compounds acting at the mTORC1 complex itself, such as rapamycin and its derivatives. Thus, testing glycineB site ligands in relevant in vitro and in vivo paradigms with established human cancer cells that express NMDA receptors on their surface could provide proofs of concept/principle that would encourage exploration of these and other "non-toxic" strategies. Interestingly, in some cancer models that express NMDA receptors on their surface, NMDA receptor antagonists, such as MK-801 (dizocilpine), were shown to possess anti-proliferative and anti-invasive effects, which conflict with hypotheses about promoting NMDA receptor activation as a cancer chemotherapeutic strategy. Whether NMDA receptor activation or antagonism is associated with anti-proliferative and anti-invasive effects may reflect differences between cancer cell lines in terms of the proteins associated with the NMDA receptors on their cell surfaces, which, in turn, could lead to different "downstream" effects on cascades of intracellular phosphorylations. Irrespective of whether activation or antagonism is associated with anti-proliferative and anti-invasive effects for specific types of cancer, data are emerging that support exploration of targeting NMDA receptors expressed on the surface of cancer cells as a therapeutic strategy.