Leigh syndrome associated with cytochrome c oxidase (COX) deficiency is a mitochondrial disorder usually caused by mutations of SURF1, a gene encoding a putative COX assembly factor. We present here a Surf1-/- recombinant mouse obtained by inserting a loxP sequence in the open reading frame of the gene. The frequency of -/-, +/+ and +/- genotypes in newborn mice followed a mendelian distribution, indicating that the ablation of Surf1 is compatible with postnatal survival. The biochemical and assembly COX defect was present in Surf1(loxP)-/- mice, but milder than in humans. Surprisingly, not only these animals failed to show spontaneous neurodegeneration at any age, but they also displayed markedly prolonged lifespan, and complete protection from Ca(2+)-dependent neurotoxicity induced by kainic acid. Experiments on primary neuronal cultures showed markedly reduced rise of cytosolic and mitochondrial Ca(2+) in Surf1(loxP)-/- neurons, and reduced mortality, compared to controls. The mitochondrial membrane potential was unchanged in KO versus wild-type neurons, suggesting that the effects of the ablation of Surf1 on Ca(2+) homeostasis, and possibly on longevity, may be independent, at least in part, from those on COX assembly and mitochondrial bioenergetics.

Several studies support currently the hypothesis that autism etiology is based on a polygenic and epistatic model. However, despite advances in epidemiological, molecular and clinical genetics, the genetic risk factors remain difficult to identify, with the exception of a few chromosomal disorders and several single gene disorders associated with an increased risk for autism. Furthermore, several studies suggest a role of environmental factors in autism spectrum disorders (ASD). First, arguments for a genetic contribution to autism, based on updated family and twin studies, are examined. Second, a review of possible prenatal, perinatal, and postnatal environmental risk factors for ASD are presented. Then, the hypotheses are discussed concerning the underlying mechanisms related to a role of environmental factors in the development of ASD in association with genetic factors. In particular, epigenetics as a candidate biological mechanism for gene × environment interactions is considered and the possible role of epigenetic mechanisms reported in genetic disorders associated with ASD is discussed. Furthermore, the example of in utero exposure to valproate provides a good illustration of epigenetic mechanisms involved in ASD and innovative therapeutic strategies. Epigenetic remodeling by environmental factors opens new perspectives for a better understanding, prevention, and early therapeutic intervention of ASD.

Zygosity diagnosis has been performed in 79 pairs of twins using three methods. Simple sequence repeat length polymorphism (SSLP) analysis allows an efficient classification (MZ or DZ) with only a few markers following a simplified technique of extraction and amplification. A method based on a full questionnaire completed by parents about twin similarity correctly classifies 97.46% of the pairs; 92.41% are correctly classified using only four questions as suggested by logistic regression analysis. The third method, using dermatoglyphic analyses, correctly classifies 86.76% of pairs. To lower the cost of DNA diagnosis we stress the possibility of limiting its use to pairs with scores in the overlap area between MZ and DZ twins with a validated questionnaire.

BackgroundReports of reduced pain sensitivity in autism have prompted opioid theories of autism and have practical care ramifications. Our objective was to examine behavioral and physiological pain responses, plasma β-endorphin levels and their relationship in a large group of individuals with autism.Methodology/Principal FindingsThe study was conducted on 73 children and adolescents with autism and 115 normal individuals matched for age, sex and pubertal stage. Behavioral pain reactivity of individuals with autism was assessed in three observational situations (parents at home, two caregivers at day-care, a nurse and child psychiatrist during blood drawing), and compared to controls during venepuncture. Plasma β-endorphin concentrations were measured by radioimmunoassay. A high proportion of individuals with autism displayed absent or reduced behavioral pain reactivity at home (68.6%), at day-care (34.2%) and during venepuncture (55.6%). Despite their high rate of absent behavioral pain reactivity during venepuncture (41.3 vs. 8.7% of controls, P<0.0001), individuals with autism displayed a significantly increased heart rate in response to venepuncture (P<0.05). Moreover, this response (Δ heart rate) was significantly greater than for controls (mean±SEM; 6.4±2.5 vs. 1.3±0.8 beats/min, P<0.05). Plasma β-endorphin levels were higher in the autistic group (P<0.001) and were positively associated with autism severity (P<0.001) and heart rate before or after venepuncture (P<0.05), but not with behavioral pain reactivity.Conclusions/SignificanceThe greater heart rate response to venepuncture and the elevated plasma β-endorphin found in individuals with autism reflect enhanced physiological and biological stress responses that are dissociated from observable emotional and behavioral reactions. The results suggest strongly that prior reports of reduced pain sensitivity in autism are related to a different mode of pain expression rather than to an insensitivity or endogenous analgesia, and do not support opioid theories of autism. Clinical care practice and hypotheses regarding underlying mechanisms need to assume that children with autism are sensitive to pain.

Several lines of evidence indicate an association between mitochondrial DNA (mtDNA) and the functioning of the nervous system. As neuronal development and structure as well as axonal and synaptic activity involve mitochondrial genes, it is not surprising that most mtDNA diseases are associated with brain disorders. Only one study has suggested an association between mtDNA and cognition, however. Here we provide direct evidence of mtDNA involvement in cognitive functioning. Total substitution of mtDNA was achieved by 20 repeated backcrosses in NZB/BlNJ (N) and CBA/H (H) mice with different mtDNA origins. All 13 mitochondrial genes were expressed in the brains of the congenic quartet. In interaction with nuclear DNA (nDNA), mtDNA modified learning, exploration, sensory development and the anatomy of the brain. The effects of mtDNA substitution persisted with age, increasing in magnitude as the mice got older. We observed different effects with input of mtDNA from N versus H mice, varying according to the phenotypes. Exchanges of mtDNA may produce phenotypes outside the range of scores observed in the original mitochondrial and nuclear combinations. These findings show that mitochondrial polymorphisms are not as neutral as was previously believed.

Autism, a pervasive developmental disorder with profound deficits in social relatedness, impairments in language and communication, and symptoms involving repetitive behaviors and restricted interests, is thought to be gene-dependent. 1-3 The well-replicated, but as yet unexplained, platelet hyperserotonemia of autism 4,5 has focused attention on the possible role of the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). Reports of other 5-HT-related abnormalities in autism 6,7 and the utility of serotonergic agents in partially ameliorating symptoms in some individuals with autism 8 have also served to increase interest in the possible involvement of 5-HT in the etiology and pathophysiology of autism. The important roles of 5-HT in neurodevelopment 9,10 and the rich serotonergic innervation of limbic areas critically involved in social and affiliative behaviors 11 have provided additional, more theoretical, bases for the 5-HT hypothesis.A wide range of 5-HT-related genes can be considered as possible candidate genes in autism. However, the 5-HT transporter gene (HTT, locus SLC6A4), encoding both the neuronal and platelet transporter, 12 is of particular interest for several reasons. Reports of a positive correlation between rates of platelet 5-HT transport and platelet levels of 5-HT 13,14 suggest that the transporter may play a part in the platelet hyperserotonemia of autism. The beneficial effects of agents that block neuronal serotonin transport 8 also focus attention on the possible role of the transporter in the pathophysiology of autism. Additionally, the reported association of a HTT promoter polymorphism with anxiety in the general population, 15 coupled with reports of higher stress responsivity in autism and an increased incidence of anxiety disorder in the families of individuals with autism, 16,17 has further stimulated interest in the HTT in autism. Most intriguing have been discrepant studies reporting preferential transmission of different alleles of the biallelic promoter region polymorphism in individuals with autism. 18,19 The promoter variant consists of a 44 base-pair deletion/insertion in a repeat region of the promoter. The deletion or short (s) allele occurs with a frequency of approximately 43%, while the long (l) form has an allele frequency of 57% in samples of predominately northern European ancestry. 15,20 It is noteworthy that the polymorphism is of apparent functional significance; native lymphoblastoid cell lines with sl or ss genotypes were reported to have approximately onehalf the rates of 5-HT transport, transporter expression, and HTT mRNA levels as those with the ll genotype. 15 After genotyping the HTT promoter alleles in a group of 69 French families with autistic children, the transmission of the alleles was examined to determine their influence on risk or susceptibility to autism. A possible modifying role of the HTT on the behavioral phenotypic expression of autism was also studied. This possibility was examined by comparing allelic transmission across severity sub...

TSHZ3, which encodes a zinc-finger transcription factor, was recently positioned as a hub gene in a module of genes with the highest expression in the developing human neocortex, but its functions remained unknown. Here, we identify TSHZ3 as the critical region for a syndrome associated with heterozygous deletions at 19q12q13.11, which includes autism spectrum disorder (ASD). In Tshz3 null mice, differentially expressed genes include layer-specific markers of cerebral cortical projection neurons (CPNs) and their human orthologues are strongly associated with ASD. Furthermore, mice heterozygous for Tshz3 deletion show functional changes at synapses established by CPNs and exhibit core ASD-like behavioral abnormalities. These findings reveal essential roles for Tshz3 in CPN development and function, whose alterations can account for ASD in the newly-defined TSHZ3 deletion syndrome.

In mammals, the circadian clocks network (central and peripheral oscillators) controls circadian rhythms and orchestrates the expression of a range of downstream genes, allowing the organism to anticipate and adapt to environmental changes. Beyond their role in circadian rhythms, several studies have highlighted that circadian clock genes may have a more widespread physiological effect on cognition, mood, and reward-related behaviors. Furthermore, single nucleotide polymorphisms in core circadian clock genes have been associated with psychiatric disorders (such as autism spectrum disorder, schizophrenia, anxiety disorders, major depressive disorder, bipolar disorder, and attention deficit hyperactivity disorder). However, the underlying mechanisms of these associations remain to be ascertained and the cause–effect relationships are not clearly established. The objective of this article is to clarify the role of clock genes and altered sleep–wake rhythms in the development of psychiatric disorders (sleep problems are often observed at early onset of psychiatric disorders). First, the molecular mechanisms of circadian rhythms are described. Then, the relationships between disrupted circadian rhythms, including sleep–wake rhythms, and psychiatric disorders are discussed. Further research may open interesting perspectives with promising avenues for early detection and therapeutic intervention in psychiatric disorders.