Translational Neuroscience Contributes to Understanding Neurodevelopmental Outcomes of Dostoyevsky's "Brothers Karamazov" With Treatment Implications.

Dostoyevsky's novels raise profound ethical, moral, philosophical and theological issues and, as a result, both he and his novels serve as fertile subjects of scholarly inquiry across a variety of academic disciplines. In particular, major characters in "The Brothers Karamazov" lend themselves to classical psychodynamic formulations, such as the influence of adverse childhood experiences on adult social and occupational outcomes, which in the case of Dmitry, the eldest son of Fyodor Pavlovich Karamazov, are considered in exquisitely fine detail. Prosecutor and defense attorney provide differing interpretations of how early traumas, largely due to paternal neglect and abuse, affected Dmitry's adult outcome in the climactic trial over his alleged patricide.

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).

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.

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.

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.

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

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.

An Evolving Therapeutic Rationale for Targeting the α 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 α nicotinic acetylcholine receptor (α nAChR), are associated with a spectrum of neurodevelopmental disorders, including 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.

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.

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.

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.

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").

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.

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.

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.

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).

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 Aβ1-42 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.

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.

Rapamycin improves sociability in the BTBR T(+)Itpr3(tf)/J mouse model of autism spectrum disorders.

Overactivation of the mammalian target of rapamycin (mTOR) has been implicated in the pathogenesis of syndromic forms of autism spectrum disorders (ASDs), such as tuberous sclerosis complex, neurofibromatosis 1, and fragile X syndrome. Administration of mTORC1 (mTOR complex 1) inhibitors (e.g.

Balb/c mice treated with D-cycloserine arouse increased social interest in conspecifics.

The genetically inbred Balb/cJ (Balb/c) mouse with functional alteration of its endogenous tone of NMDA receptor-mediated neurotransmission displays impaired sociability in a standard paradigm; this mouse strain has been proposed as a model of autism spectrum disorders (ASDs). Prior work showed that treatment of the Balb/c mouse with a centrally effective dose of D-cycloserine, a partial glycineB NMDA receptor agonist, improved several measures of its sociability. Additionally, D-cycloserine-treated Balb/c mice show greater preference for a social stimulus mouse than an inanimate object.

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.

D-Cycloserine improves sociability in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorders with altered Ras/Raf/ERK1/2 signaling.

The genetically inbred BTBR T+ Itpr3tf/J (BTBR) mouse is a proposed model of autism spectrum disorders (ASDs). Similar to several syndromic forms of ASDs, mTOR activity may be enhanced in this mouse strain as a result of increased Ras signaling. Recently, D-cycloserine, a partial glycineB site agonist that targets the NMDA receptor, was shown to improve the sociability of the Balb/c mouse strain, another proposed genetically inbred model of ASDs.