1. Calahorro F, Ruiz-Rubio M. {{Caenorhabditis elegans as an experimental tool for the study of complex neurological diseases: Parkinson’s disease, Alzheimer’s disease and autism spectrum disorder}}. {Invert Neurosci};2011 (Nov 8)
The nematode Caenorhabditis elegans has a very well-defined and genetically tractable nervous system which offers an effective model to explore basic mechanistic pathways that might be underpin complex human neurological diseases. Here, the role C. elegans is playing in understanding two neurodegenerative conditions, Parkinson’s and Alzheimer’s disease (AD), and a complex neurological condition, autism, is used as an exemplar of the utility of this model system. C. elegans is an imperfect model of Parkinson’s disease because it lacks orthologues of the human disease-related genes PARK1 and LRRK2 which are linked to the autosomal dominant form of this disease. Despite this fact, the nematode is a good model because it allows transgenic expression of these human genes and the study of the impact on dopaminergic neurons in several genetic backgrounds and environmental conditions. For AD, C. elegans has orthologues of the amyloid precursor protein and both human presenilins, PS1 and PS2. In addition, many of the neurotoxic properties linked with Abeta amyloid and tau peptides can be studied in the nematode. Autism spectrum disorder is a complex neurodevelopmental disorder characterised by impairments in human social interaction, difficulties in communication, and restrictive and repetitive behaviours. Establishing C. elegans as a model for this complex behavioural disorder is difficult; however, abnormalities in neuronal synaptic communication are implicated in the aetiology of the disorder. Numerous studies have associated autism with mutations in several genes involved in excitatory and inhibitory synapses in the mammalian brain, including neuroligin, neurexin and shank, for which there are C. elegans orthologues. Thus, several molecular pathways and behavioural phenotypes in C. elegans have been related to autism. In general, the nematode offers a series of advantages that combined with knowledge from other animal models and human research, provides a powerful complementary experimental approach for understanding the molecular mechanisms and underlying aetiology of complex neurological diseases.
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2. Courchesne E, Mouton PR, Calhoun ME, Semendeferi K, Ahrens-Barbeau C, Hallet MJ, Barnes CC, Pierce K. {{Neuron number and size in prefrontal cortex of children with autism}}. {JAMA};2011 (Nov 9);306(18):2001-2010.
CONTEXT: Autism often involves early brain overgrowth, including the prefrontal cortex (PFC). Although prefrontal abnormality has been theorized to underlie some autistic symptoms, the cellular defects that cause abnormal overgrowth remain unknown. OBJECTIVE: To investigate whether early brain overgrowth in children with autism involves excess neuron numbers in the PFC. DESIGN, SETTING, AND CASES: Postmortem prefrontal tissue from 7 autistic and 6 control male children aged 2 to 16 years was examined by expert anatomists who were blinded to diagnostic status. Number and size of neurons were quantified using stereological methods within the dorsolateral (DL-PFC) and mesial (M-PFC) subdivisions of the PFC. Cases were from the eastern and southeastern United States and died between 2000 and 2006. MAIN OUTCOME MEASURES: Mean neuron number and size in the DL-PFC and M-PFC were compared between autistic and control postmortem cases. Correlations of neuron number with deviation in brain weight from normative values for age were also performed. RESULTS: Children with autism had 67% more neurons in the PFC (mean, 1.94 billion; 95% CI, 1.57-2.31) compared with control children (1.16 billion; 95% CI, 0.90-1.42; P = .002), including 79% more in DL-PFC (1.57 billion; 95% CI, 1.20-1.94 in autism cases vs 0.88 billion; 95% CI, 0.66-1.10 in controls; P = .003) and 29% more in M-PFC (0.36 billion; 95% CI, 0.33-0.40 in autism cases vs 0.28 billion; 95% CI, 0.23-0.34 in controls; P = .009). Brain weight in the autistic cases differed from normative mean weight for age by a mean of 17.6% (95% CI, 10.2%-25.0%; P = .001), while brains in controls differed by a mean of 0.2% (95% CI, -8.7% to 9.1%; P = .96). Plots of counts by weight showed autistic children had both greater total prefrontal neuron counts and brain weight for age than control children. CONCLUSION: In this small preliminary study, brain overgrowth in males with autism involved an abnormal excess number of neurons in the PFC.
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3. Lainhart JE, Lange N. {{Increased neuron number and head size in autism}}. {JAMA};2011 (Nov 9);306(18):2031-2032.
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4. Munshi KR, Gonzalez-Heydrich J, Augenstein T, D’Angelo EJ. {{Evidence-based treatment approach to autism spectrum disorders}}. {Pediatr Ann};2011 (Nov);40(11):569-574.
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5. Olmos-Serrano JL, Corbin JG, Burns MP. {{The GABA(A) Receptor Agonist THIP Ameliorates Specific Behavioral Deficits in the Mouse Model of Fragile X Syndrome}}. {Dev Neurosci};2011 (Nov 8)
Hyperactivity, hypersensitivity to auditory stimuli, and exaggerated fear are common behavioral abnormalities observed in individuals with fragile X syndrome (FXS), a neurodevelopmental disorder that is the most common genetic cause of autism. Evidence from studies of the Fmr1 knockout (KO) mouse model of FXS supports the notion that impaired GABAergic transmission in different brain regions such as the amygdala, striatum or cerebral cortex is central to FXS behavioral abnormalities. This suggests that the GABAergic system might be an intriguing target to ameliorate some of the phenotypes in FXS. Our recent work revealed that THIP (gaboxadol), a GABA(A) receptor agonist, can restore principal neuron excitability deficits in the Fmr1 KO amygdala, suggesting that THIP may also restore some of the key behavioral abnormalities in Fmr1 KO mice. Here, we reveal that THIP significantly attenuated hyperactivity in Fmr1 KO mice, and reduced prepulse inhibition in a volume-dependent manner. In contrast, THIP did not reverse the deficits in cued fear or startle response. Thus, this study shows that enhancing GABAergic transmission can correct specific behavioral phenotypes of the Fmr1 KO mouse further supporting that targeting the GABAergic system, and specifically tonic inhibition, might be important for correcting or ameliorating some key behaviors in FXS.
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6. Saalasti S, Katsyri J, Tiippana K, Laine-Hernandez M, von Wendt L, Sams M. {{Audiovisual Speech Perception and Eye Gaze Behavior of Adults with Asperger Syndrome}}. {J Autism Dev Disord};2011 (Nov 9)
Audiovisual speech perception was studied in adults with Asperger syndrome (AS), by utilizing the McGurk effect, in which conflicting visual articulation alters the perception of heard speech. The AS group perceived the audiovisual stimuli differently from age, sex and IQ matched controls. When a voice saying /p/ was presented with a face articulating /k/, the controls predominantly heard /k/. Instead, the AS group heard /k/ and /t/ with almost equal frequency, but with large differences between individuals. There were no differences in gaze direction or unisensory perception between the AS and control participants that could have contributed to the audiovisual differences. We suggest an explanation in terms of weak support from the motor system for audiovisual speech perception in AS.
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7. Siegel M, Beaulieu AA. {{Psychotropic Medications in Children with Autism Spectrum Disorders: A Systematic Review and Synthesis for Evidence-Based Practice}}. {J Autism Dev Disord};2011 (Nov 9)
This paper presents a systematic review, rating and synthesis of the empirical evidence for the use of psychotropic medications in children with autism spectrum disorders (ASD). Thirty-three randomized controlled trials (RCTs) published in peer-reviewed journals qualified for inclusion and were coded and analyzed using a systematic evaluative method specific to autism research (Reichow et al. in Journal of Autism and Developmental Disorders 38:1311-1319, 2008). Results are presented by agent and primary target symptom(s). The findings suggest established evidence for relatively few agents, with preliminary and promising evidence for a larger group. Challenges and opportunities in the developing field of ASD psychopharmacology are identified, and recommendations for further research are provided.
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8. Watson LR, Roberts JE, Baranek GT, Mandulak KC, Dalton JC. {{Behavioral and Physiological Responses to Child-Directed Speech of Children with Autism Spectrum Disorders or Typical Development}}. {J Autism Dev Disord};2011 (Nov 10)
Young boys with autism were compared to typically developing boys on responses to nonsocial and child-directed speech (CDS) stimuli. Behavioral (looking) and physiological (heart rate and respiratory sinus arrhythmia) measures were collected. Boys with autism looked equally as much as chronological age-matched peers at nonsocial stimuli, but less at CDS stimuli. Boys with autism and language age-matched peers differed in patterns of looking at live versus videotaped CDS stimuli. Boys with autism demonstrated faster heart rates than chronological age-matched peers, but did not differ significantly on respiratory sinus arrhythmia. Reduced attention during CDS may restrict language-learning opportunities for children with autism. The heart rate findings suggest that young children with autism have a nonspecific elevated arousal level.
