Maria R. Urbano

A trial of D-cycloserine to treat stereotypies in older adolescents and young adults with autism spectrum disorder.

ObjectivesAutism spectrum disorders (ASDs) have core impairments in social communication as well as the presence of repetitive, stereotypic behaviors and restricted interests. Older adolescents and young adults are particularly impacted by these deficits. Preclinical data implicate glutamatergic dysfunction in the pathophysiology of ASDs. D-Cycloserine (DCS), a partial glycineB agonist at the N-methyl-D-aspartic acid receptor site, has been shown to improve sociability in mouse models and a small human study. The sensitivity of the obligatory glycineB co-agonist binding site may change with daily administration of DCS as a result of agonist-induced desensitization. The efficacy of a “pulsed” once-weekly administration versus “daily” administration of DCS was compared. MethodsMales and females, ages 14 to 25 years, with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision diagnosis of an ASD were enrolled in a double-blind, randomized 10-week trial consisting of 8 weeks of active drug with either weekly or daily administration of 50 mg of DCS followed by a 2-week follow-up visit. ResultsFor the purposes of this study, no statistical or clinical differences existed between the 2 dosage groups on the Aberrant Behavior Checklist subscale 3, which measures stereotypies/repetitive movements. When combining groups, a statistically significant decrease of 37% was found from baseline to week 8 when study drug was completed using a linear mixed effects model (P = 0.003). ConclusionsD-Cycloserine was shown to be effective in improving stereotypic symptoms in older adolescents and young adults with ASDs measured by the Aberrant Behavior Checklist subscale 3. In addition, DCS was safe and well tolerated.

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.

Pharmacotherapeutic implications of the association between genomic instability at chromosome 15q13.3 and autism spectrum disorders.

Abstract Recurrent microdeletions of chromosome 15q13.3 are causally associated with autism spectrum disorders (ASDs), suggesting that haploinsufficiency of CHRNA7, the gene that codes for the &agr;7 nicotinic acetylcholine receptor (&agr;7 nAChR) subunit, is an etiological mechanism. Independent of these genetic data, given the location of &agr;7 nAChRs on &ggr;-aminobutyric acid–inhibitory neurons and their role in maintaining central inhibitory tone, a compelling pharmacological rationale exists for therapeutically targeting the &agr;7 nAChR in persons with ASDs. Given the availability of positive allosteric modulators of nicotinic acetylcholine receptors and selective agonists for the &agr;7 nAChR (eg, choline derived from dietary administration of cytidine 5’diphosphocholine and anabasine derivatives), it is possible to conduct “proof of concept” clinical trials, exploring the effects of &agr;7 nAChR agonist interventional strategies on domains of psychopathology, such as attention, cognition, and memory, in persons with ASDs.

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 receptors 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 Alzheimers 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 Aβ1-42 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 Aβ1-42 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/β-catenin signaling cascade and both transcriptional and non-transcriptional effects of β-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.

Impaired Sociability of the Balb/c Mouse, an Animal Model of Autism Spectrum Disorders, is Attenuated by NMDA Receptor Agonist Interventions: Clinical Implications

Impaired sociability is a domain of psychopathology that contributes significantly to the functional disability and poor quality of life of persons with Autism Spectrum Disorders (ASDs) (Brodkin, 2007; Crawley, 2004, 2007; Deutsch et al., 2011). Although cognitive functioning may influence the expression of impaired sociability, the relationship between cognitive deficits and impaired sociability is not a linear one; thus, for example, persons with ASDs whose IQs are in the near-normal to above normal range may manifest profound deficits of sociability that are similar to those shown by persons with ASDs and intellectual disability (Noterdaeme et al., 2010). Currently, there are no approved medications whose primary target is the domain of impaired sociability. The N-methyl-D-aspartic acid (NMDA) receptor is an example of a glutamate-gated ion channel that is comprised of four (or possibly five) constituent polypeptide subunits; it is located both preand postsynaptically (Millian, 2005). Each constituent polypeptide is an integral membrane protein that has external, transmembranous and internal domains. The constituent polypeptides align themselves within the lipid bilayer of the membrane to create a potential channel, whose opening depends on the membrane potential and the binding of L-glutamate and glycine. The duration and frequency of channel opening, which results in calcium ion conductance and membrane depolarization, are highly regulated. The properties of this ligand-gated ion channel receptor are influenced genetically by the combinatorial diversity of the constituent polypeptide subunits (i.e., expression and membrane insertion of specific subunits and their splice variants can affect channel properties); allosteric modulatory ligands (e.g., neurosteroids) (Deutsch et al., 1992); the extent to which the receptor is glycosylated and nitrosylated; and the extent to which the internal domain of receptor polypeptide subunits are phosphorylated (Marino & Conn, 2002). The phosphorylation state of the internal domain is influenced by cross-talk between specific signaling pathways and the NMDA receptor; for example, stimulation of metabotropic glutamate receptors co-localized with NMDA receptors on the cell surface can influence the extent of phosphorylation (Conn et al., 2009a; Marino & Conn, 2002). When the

Relationships, Sexuality, and Intimacy in Autism Spectrum Disorders

The purpose of this chapter is to provide a brief overview of Autism Spectrum Disorders (ASD) and sexuality, as there is a paucity of this information in the literature. Specific attention is giv‐ en to sexuality involving the self, others, and interpersonal relationships. Problematic sexual behaviors, legal concerns, and sexual abuse (including victimization and perpetration) are also discussed. Finally, intervention strategies for ASD children, adults, and families are addressed. The overall aim of this chapter is to highlight major themes regarding Autism Spectrum Disor‐ ders and sexuality while contributing to the existing literature.

Clinical considerations for the inclusion of individuals with autism spectrum disorder in clinical trials

ABSTRACT Diagnoses of autism spectrum disorder (ASD) have increased considerably over the past 20years. Because of this rise and the inherent complexity of ASD, there is a need for an increased number of scientifically valid basic and clinical research studies addressing this disorder. This manuscript serves as an introduction to the clinical presentation of ASD as well as the unique challenges and modifications required to conduct clinical research with this population. This includes detailing the current diagnostic criteria, process of receiving an ASD diagnosis, information on assessment measures, and special considerations when developing research. It is the hope that this information will provide researchers interested in conducting clinical trials with those with ASD with baseline information and considerations when developing their research topics and methodology. HIGHLIGHTSResearch with Autism Spectrum Disorder (ASD) requires special consideration.There are major differences between DSM‐IV and DSM5 diagnoses.Specific diagnostic, clinical, and research assessment measures are used.Co‐morbidities are common in ASD and may impact research.Research procedures may involve modification due to ASD traits.

Autism spectrum disorder in Latin American families: Experiences in Chile.

Introduction: The present study provides pilot data investigating relationships between severity of autism spectrum disorder (ASD) traits, community supports, and other family variables as reported by caregivers of children with ASD in Chile. Method: An anonymous caregiver survey was developed based on previous ASD survey studies conducted in the United States and direct input from collaborators residing in Chile. Participants included Chilean caregivers of individuals with ASD (N = 50; Mchild age = 6.98). The survey addressed topics regarding the child’s ASD traits, the caregiver’s beliefs and perceptions of ASD, and community supports and engagement. Results: Correlational analyses indicated associations between ASD traits, physician support, family stress, stigma, and community engagement. Discussion: Results from this study highlight the importance of future research to better understand and treat Latin American children with ASD and their families.

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

Abstract 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.