Sunday, December 25, 2016

D-cycloserine boosting social behavior in autism

It may be possible to boost social interaction in people with autism by using a new therapeutic drug target, University of Pennsylvania researchers say.

The researchers from Penn’s Perelman School of Medicine used mouse models of autism in order to examine the gene called Protocadherin 10 (PCDH10). The gene, as the researchers described in a press release, is a neural cell adhesion molecule involved in both brain development and maintenance of neural synapses. While there are medications available for people with autism to treat associated symptoms like anxiety, depression, attention deficit hyperactivity disorder (ADHD), and irritability, there is nothing currently approved for social interactions.

"This research could significantly change our understanding of the causes and brain changes in autism and could lead to new treatment approaches for the harder to treat social aspects of ASD," senior author Edward S. Brodkin, MD, said in the statement.

The investigators deleted one of the two copies of PCDH10 from the mice, they showed decreased social approach behaviors. The researchers also noted that this habit was observed more often in males than females, which seemed consistent with understood behaviors of autism in humans. The mice with one deleted PCDH10 gene also showed differences in the structure and abilities of the amygdala, the researchers said.

In order to remedy the social behavioral deficits, the researchers administered d-cycloserine to the male mice to bind glycine to NMDA receptors and increase glutamate signaling at the receptors. "By enhancing NMDA receptor signaling, the mice went from social avoidance to more typical social approach behavior," Brodkin observed.

Again, the researchers said this finding was in line with what has been observed in small, preliminary clinical studies of human patients with autism. In these studies, d-cycloserine was seen to significantly boost social behaviors in older adolescents and young adults who were diagnosed with autism spectrum disorders. The researchers believe their findings can lend credibility to these small human studies and provide a kickstart for other investigators to continue this work in human patients.

In the future, Brodkin and his team plan to continue to use mice models of autism to understand why the presence or absence of PCDH10 seems to affect males more than females in terms of social behaviors. The researchers want to continue to learn more about these behaviors and how they are affected by the amygdala to point toward better future treatment approaches for social behaviors in certain autism spectrum disorder subtypes.

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Schoch H, Kreibich AS, Ferri SL, White RS, Bohorquez D, Banerjee A, Port RG, Dow HC, Cordero L, Pallathra AA, Kim H, Li H, Bilker WB, Hirano S, Schultz RT, Borgmann-Winter K, Hahn CG, Feldmeyer D, Carlson GC, Abel T, Brodkin ES. Sociability Deficits and Altered Amygdala Circuits in Mice Lacking Pcdh10, an Autism Associated Gene. Biol Psychiatry. 2016 Jun 16. pii: S0006-3223(16)32474-X. doi: 10.1016/j.biopsych.2016.06.008. [Epub ahead of print]

Abstract
BACKGROUND:
Behavioral symptoms in individuals with autism spectrum disorder (ASD) have been attributed to abnormal neuronal connectivity, but the molecular bases of these behavioral and brain phenotypes are largely unknown. Human genetic studies have implicated PCDH10, a member of the δ2 subfamily of nonclustered protocadherin genes, in ASD. PCDH10 expression is enriched in the basolateral amygdala, a brain region implicated in the social deficits of ASD. Previous reports indicate that Pcdh10 plays a role in axon outgrowth and glutamatergic synapse elimination, but its roles in social behaviors and amygdala neuronal connectivity are unknown. We hypothesized that haploinsufficiency of Pcdh10 would reduce social approach behavior and alter the structure and function of amygdala circuits.
METHODS:
Mice lacking one copy of Pcdh10 (Pcdh10+/-) and wild-type littermates were assessed for social approach and other behaviors. The lateral/basolateral amygdala was assessed for dendritic spine number and morphology, and amygdala circuit function was studied using voltage-sensitive dye imaging. Expression of Pcdh10 and N-methyl-D-aspartate receptor (NMDAR) subunits was assessed in postsynaptic density fractions of the amygdala.
RESULTS:
Male Pcdh10+/- mice have reduced social approach behavior, as well as impaired gamma synchronization, abnormal spine morphology, and reduced levels of NMDAR subunits in the amygdala. Social approach deficits in Pcdh10+/- male mice were rescued with acute treatment with the NMDAR partial agonist d-cycloserine.
CONCLUSIONS:
Our studies reveal that male Pcdh10+/- mice have synaptic and behavioral deficits, and establish Pcdh10+/- mice as a novel genetic model for investigating neural circuitry and behavioral changes relevant to ASD.

6 comments:

  1. Minshawi NF, Wink LK, Shaffer R, Plawecki MH, Posey DJ, Liu H, Hurwitz S, McDougle CJ, Swiezy NB, Erickson CA. A randomized, placebo-controlled trial of D-cycloserine for the enhancement of social skills training in autism spectrum disorders. Mol Autism. 2016 Jan 14;7:2.

    Abstract
    BACKGROUND:
    Researchers have demonstrated that d-cycloserine (DCS) can enhance the effects of behavioral interventions in adults with anxiety and enhances prosocial behavior in animal models of autism spectrum disorders (ASD). This study extended upon this background by combining DCS with behavioral social skills therapy in youth with ASD to assess its impact on the core social deficits of ASD. We hypothesized that DCS used in combination with social skills training would enhance the acquisition of social skills in children with ASD.
    METHODS:
    A 10-week, double-blind, placebo-controlled trial of DCS (50 mg) given 30 min prior to weekly group social skills training was conducted at two sites. Children with ASD were randomized to receive 10 weeks (10 doses) of DCS or placebo in a 1:1 ratio.
    RESULTS:
    No statistically significant difference attributable to drug treatment was observed in the change scores for the primary outcome measure, the Social Responsiveness Scale (SRS), total score (p = 0.45), or on secondary outcome measures.
    CONCLUSIONS:
    The results of this trial demonstrated no drug-related short-term improvement on the primary outcome measure, or any of the secondary outcome measures. However, an overall significant improvement in SRS total raw score was observed from baseline to end of treatment for the entire group of children with ASD. This suggests a need to further study the efficacy of the social skills training protocol. Limitations to the current study and areas for future research are discussed.

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  2. Urbano M, Okwara L, Manser P, Hartmann K, Deutsch SI. A trial of d-cycloserine to treat the social deficit in older adolescents and young adults with autism spectrum disorders. J Neuropsychiatry Clin Neurosci. 2015;27(2):133-8.

    Abstract
    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.

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  3. Wellmann KA, Varlinskaya EI, Mooney SM. D-Cycloserine ameliorates social alterations that result from prenatal exposure to valproic acid. Brain Res Bull. 2014 Sep;108:1-9.

    Abstract
    Prenatal exposure to valproic acid (VPA) alters rodent social interactions in a dose-dependent way: exposure to a high dose of VPA (>500 mg/kg) mid-gestation decreases social interactions whereas a moderate dose of VPA (350 mg/kg) increases peer-directed social behavior. The moderate dose also decreases expression of the mRNA for serine in amygdala and orbitofrontal cortex. In this study, we examined whether d-cycloserine could ameliorate VPA-induced alterations in ultrasonic vocalizations (USVs), social interactions, and locomotor activity. Pregnant Sprague Dawley rats were given intraperintoneal injections of VPA (200mg/kg each) on gestational days 12, 12.5 and 13; controls were injected with saline. Offspring received a subcutaneous injection of saline or d-cycloserine (32 or 64 mg/kg) either acutely (1h prior to testing) or repeatedly (once per day for four days). Social interactions were assessed during late adolescence, and USVs were recorded concomitantly. Male and female rats that were exposed to VPA demonstrated more locomotor activity than control animals during habituation to the testing chamber. VPA-exposed males showed increased play fighting. d-Cycloserine normalized the VPA-induced increase in play fighting in males and also increased social motivation in females. When the pair contained a VPA-exposed rat, significantly fewer USVs were emitted and 16% of the vocalizations were of a novel waveform. These effects were not seen in pairs containing VPA-exposed animals that were treated with d-cycloserine. Overall, these findings are consistent with data from other laboratories suggesting that d-cycloserine may be a promising pharmacotherapeutic compound for improving social behavior disorders.

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  4. Urbano M, Okwara L, Manser P, Hartmann K, Herndon A, Deutsch SI. A trial of D-cycloserine to treat stereotypies in older adolescents and young adults with autism spectrum disorder. Clin Neuropharmacol. 2014 May-Jun;37(3):69-72.

    Abstract
    OBJECTIVES:
    Autism 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.
    METHODS:
    Males 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.
    RESULTS:
    For 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).
    CONCLUSIONS:
    D-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.

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  5. Burket JA, Benson AD, Tang AH, Deutsch SI. D-Cycloserine improves sociability in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorders with altered Ras/Raf/ERK1/2 signaling. Brain Res Bull. 2013 Jul;96:62-70.

    Abstract
    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. NMDA receptor activation is an important regulator of mTOR signaling activity. Given the ability of D-cycloserine to improve the sociability of the Balb/c mouse strain and the regulatory role of the NMDA receptor in mTOR signaling, we wondered if D-cycloserine would improve the impaired sociability of the BTBR mouse strain. D-Cycloserine (320 mg/kg, ip) improved measures of sociability in a standard sociability paradigm and spontaneous grooming that emerged during social interaction with an ICR stimulus mouse in the BTBR strain; however, similar effects were observed in the Swiss Webster comparator strain, raising questions about their strain-selectivity. Importantly, the profile of D-cycloserine's effects on both measures of sociability and stereotypies is consistent with that of a desired medication for ASDs; specifically, a desired medication would not improve sociability at the expense of worsening stereotypic behaviors or vice versa.

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  6. Schade S, Paulus W. D-Cycloserine in Neuropsychiatric Diseases: A Systematic Review. Int J Neuropsychopharmacol. 2016 Apr 20;19(4).

    Abstract
    D-Cycloserine, known from tuberculosis therapy, has been widely introduced to neuropsychiatric studies, since its central active mechanism as a partial NMDA-agonist has been found. In this review, we evaluate its therapeutic potential in neuropsychological disorders and discuss its pitfalls in terms of dosing and application frequency as well as its safety in low-dose therapy. Therefore, we identified 91 clinical trials by performing a Medline search. We demonstrate in part preliminary but increasing evidence that D-cycloserine may be effective in various psychiatric diseases, including schizophrenia, anxiety disorders, addiction, eating disorders, major depression, and autism as well as in neurological diseases, including dementia, Alzheimer's disease, and spinocerebellar degeneration. D-Cycloserine in low-dose therapy is safe, but there is still a need for new drugs with higher specificity to the different N-methyl-D-aspartate-receptor subunits.

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