Amy L. Herndon

d-cycloserine improves sociability and spontaneous stereotypic behaviors in 4-week old mice

Balb/c mice are a model of impaired sociability and social motivation relevant to autism spectrum disorders (ASDs). Impaired sociability of 8-week old Balb/c mice is attenuated by agonists of the glycine(B) site on the NMDA receptor, such as d-cycloserine. Although ASDs are often recognized in toddlerhood, there is interest in earlier identification (e.g., before 6 months) and disease-modifying interventions to improve functional outcomes. Thus, we wondered if d-cycloserine could improve sociability in 4-week old Balb/c mice, similar to its effects in 8-week old mice. d-Cycloserine improved measures of impaired sociability in 4-week old (i.e., one-week post-weanling) Balb/c mice. Moreover, because stereotypies can compete with the salience of social stimuli, we compared Balb/c and Swiss Webster mice on several spontaneous stereotypic behaviors emerging during social interaction with a social stimulus mouse. Interestingly, similar to 8-week old mice, spontaneous stereotypic behaviors during social interaction were more intense in the 4-week old Swiss Webster mice; furthermore, d-cycloserine reduced their intensity. Thus, d-cycloserine improves both sociability and stereotypic behaviors, but these effects may lack strain-selectivity. A prosocial effect of d-cycloserine was observed at a dose as low as 32.0mg/kg in Balb/c mice. d-cycloserine has the therapeutic properties of a desired medication for ASDs; specifically, a medication should not improve stereotypic behaviors at the expense of worsening sociability and vice versa. The data suggest that targeting the NMDA receptor can have promising therapeutic effects on two prominent domains of psychopathology in ASDs: impaired sociability and spontaneous stereotypic behaviors.

Genetically inbred Balb/c mice differ from outbred Swiss Webster mice on discrete measures of sociability: relevance to a genetic mouse model of autism spectrum disorders

The Balb/c mouse is proposed as a model of human disorders with prominent deficits of sociability, such as autism spectrum disorders (ASDs) that may involve pathophysiological disruption of NMDA receptor‐mediated neurotransmission. A standard procedure was used to measure sociability in 8‐week‐old male genetically inbred Balb/c and outbred Swiss Webster mice. Moreover, because impaired sociability may influence the social behavior of stimulus mice, we also measured the proportion of total episodes of social approach made by the stimulus mouse while test and stimulus mice were allowed to interact freely. Three raters with good inter‐rater agreement evaluated operationally defined measures of sociability chosen because of their descriptive similarity to deficits of social behavior reported in persons with ASDs. The data support previous reports that the Balb/c mouse is a genetic mouse model of impaired sociability. The data also show that the behavior of the social stimulus mouse is influenced by the impaired sociability of the Balb/c strain. Interestingly, operationally defined measures of sociability did not necessarily correlate with each other within mouse strain and the profile of correlated measures differed between strains. Finally, “stereotypic” behaviors (i.e. rearing, grooming and wall climbing) recorded during the session of free interaction between the test and social stimulus mice were more intensely displayed by Swiss Webster than Balb/c mice, suggesting that the domains of sociability and “restricted repetitive and stereotyped patterns of behavior” are independent of each other in the Balb/c strain. Autism Res 2011,4:393–400.

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.

d-Cycloserine improves the impaired sociability of the Balb/c mouse

The genetically inbred Balb/c mouse strain shows evidence of impaired sociability in a standard paradigm. For example, relative to 8-week-old male outbred Swiss-Webster mice, 8 week-old male Balb/c mice spend less time sniffing and in the vicinity of an enclosed 4 week-old male ICR stimulus mouse and, when allowed to interact freely with the stimulus mouse for five minutes, make fewer discrete episodes of social approach and show suppression of locomotor activity. We explored the effect of D-cycloserine (320mg/kg, intraperitoneally), a partial glycine agonist that binds to the obligatory co-agonist glycine binding site on the NMDA receptor, on the sociability of the Balb/c and Swiss-Webster mouse strains in a standard paradigm. The results show that treatment with D-cycloserine increased the locomotor activity of the Balb/c mouse strain in the presence of an enclosed social stimulus mouse and when these mice were allowed to interact freely with each other. Also, D-cycloserine increased the number of discrete episodes of social approach when Balb/c mice were allowed to interact freely with social stimulus mice. However, D-cycloserine had similar effects on measures of sociability in the Swiss-Webster mouse, raising the possibility that the positive effects on the sociability of the Balb/c mouse strain may be mediated by indirect effects on locomotion, arousal, and anxiety.

D-Cycloserine enhances social exploration in the Balb/c mouse.

Inbred Balb/c mice show deficits of sociability. The endogenous tone of NMDA receptor-mediated neurotransmission is altered in Balb/c mice, which may explain the beneficial effect of D-cycloserine on impaired sociability. In the current study, Balb/c mice spent more time than the Swiss Webster comparator strain in the open arms of an elevated plus maze (EPM), suggesting that they are not more anxious or fearful in the absence of a social stimulus mouse. Moreover, Balb/c and Swiss Webster mice did not differ in the amount of time they spent exploring an inanimate object in an open field. Differences in exploratory activity between strains emerged only when a salient social stimulus mouse was enclosed in the open field. D-Cycloserine increased the amount of time Balb/c mice spent exploring the enclosed stimulus mouse to levels observed in vehicle-treated Swiss Webster mice. Finally, irrespective of strain, D-cycloserine increased exploratory activity as measured in open arm entries in the EPM, when no enclosed stimulus mouse was present. The data show that mouse strain influences D-cycloserines effect on exploration in the presence of a salient social stimulus mouse. In the absence of an enclosed stimulus mouse, D-cycloserine increased open arm entries significantly in both the sociability-impaired Balb/c and comparator Swiss Webster strains. Thus, D-cycloserine positively affects exploratory activity in general, but strain differences emerge when the stimulus eliciting exploration is a salient social stimulus mouse versus an inanimate object. Further, the sociability deficit of the Balb/c mouse is not an epiphenomenon of increased generalized anxiety.

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.

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