Construct Validity and Cross Validity of a Test Battery Modeling Autism Spectrum Disorder (ASD) in Mice.

Modeling in other organism species is one of the crucial stages in ascertaining the association between gene and psychiatric disorder. Testing Autism Spectrum Disorder (ASD) in mice is very popular but construct validity of the batteries is not available. We presented here the first factor analysis of a behavioral model of ASD-like in mice coupled with empirical validation. We defined fourteen measures aligning mouse-behavior measures with the criteria defined by DSM-5 for the diagnostic of ASD. Sixty-five mice belonging to a heterogeneous pool of genotypes were tested. Reliability coefficients vary from .68 to .81. The factor analysis resulted in a three- factor solution in line with DSM criteria: social behavior, stereotypy and narrowness of the field of interest. The empirical validation with mice sharing a haplo-insufficiency of the zinc-finger transcription factor TSHZ3/Tshz3 associated with ASD shows the discriminant power of the highly loaded items.

Differential Brain, Cognitive and Motor Profiles Associated with Partial Trisomy. Modeling Down Syndrome in Mice.

We hypothesize that the trisomy 21 (Down syndrome) is the additive and interactive outcome of the triple copy of different regions of HSA21. Because of the small number of patients with partial trisomy 21, we addressed the question in the Mouse in which three chromosomal regions located on MMU10, MMU17 and MMU16 carries almost all the HSA21 homologs. Male mice from four segmental trisomic strains covering the D21S17-ETS2 (syntenic to MMU16) were examined with an exhaustive battery of cognitive tests, motor tasks and MRI and compared with TS65Dn that encompasses D21S17-ETS2. None of the four strains gather all the impairments (measured by the effect size) of TS65Dn strain. The 152F7 strain was close to TS65Dn for motor behavior and reference memory and the three other strains 230E8, 141G6 and 285E6 for working memory. Episodic memory was impaired only in strain 285E6. The hippocampus and cerebellum reduced sizes that were seen in all the strains indicate that trisomy 21 is not only a hippocampus syndrome but that it results from abnormal interactions between the two structures.

Social Comparison Orientation in Monozygotic and Dizygotic Twins.

Twin research has offered evidence that monozygotic (MZ) twins are more socially close than dizygotic (DZ) twins, but has not paid much attention to the way twins compare themselves with their co-twin. The few studies in this area suggest that 'horizontal comparisons' (social comparison motivated by solidarity or communion with others) matter more for MZ twins than for DZ twins, at least when the co-twin is the social comparison standard. Consistent with this view, we predicted higher interest in MZ twins relative to DZ twins to select their co-twin rather than other people in general as the social comparison standard. The Social Comparison Orientation (SCO) scale, which measures the inclination to compare with others in a horizontal rather than vertical mode (comparing either upward or downward), was administered in 90 MZ pairs and 57 same-sex DZ pairs (63% female; average age 18.06 years) from the Netherlands Twin Register. MZ twin pairs showed significantly higher SCO scores than DZ twin pairs (with a large effect size) on the co-twin SCO, whereas the two groups did not differ from each other on the general SCO excluding the co-twin as social comparison standard. In MZ twin pairs, anxiety was associated with social comparison with others in general, not with their co-twin. For both scales, twin resemblance was explained by additive genetic variance. The present findings provide direct evidence that horizontal comparisons with the co-twin are of particular importance for MZ twins.

Mitochondrial DNA modifies cognition in interaction with the nuclear genome and age in mice.

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.

Targeted Tshz3 deletion in corticostriatal circuit components segregates core autistic behaviors.

We previously linked TSHZ3 haploinsufficiency to autism spectrum disorder (ASD) and showed that embryonic or postnatal Tshz3 deletion in mice results in behavioral traits relevant to the two core domains of ASD, namely social interaction deficits and repetitive behaviors. Here, we provide evidence that cortical projection neurons (CPNs) and striatal cholinergic interneurons (SCINs) are two main and complementary players in the TSHZ3-linked ASD syndrome. In the cerebral cortex, TSHZ3 is expressed in CPNs and in a proportion of GABAergic interneurons, but not in cholinergic interneurons or glial cells. In the striatum, TSHZ3 is expressed in all SCINs, while its expression is absent or partial in the other main brain cholinergic systems. We then characterized two new conditional knockout (cKO) models generated by crossing Tshz3flox/flox with Emx1-Cre (Emx1-cKO) or Chat-Cre (Chat-cKO) mice to decipher the respective role of CPNs and SCINs. Emx1-cKO mice show altered excitatory synaptic transmission onto CPNs and impaired plasticity at corticostriatal synapses, with neither cortical neuron loss nor abnormal layer distribution. These animals present social interaction deficits but no repetitive patterns of behavior. Chat-cKO mice exhibit no loss of SCINs but changes in the electrophysiological properties of these interneurons, associated with repetitive patterns of behavior without social interaction deficits. Therefore, dysfunction in either CPNs or SCINs segregates with a distinct ASD behavioral trait. These findings provide novel insights onto the implication of the corticostriatal circuitry in ASD by revealing an unexpected neuronal dichotomy in the biological background of the two core behavioral domains of this disorder.

Laterality preference and cognition: cross-syndrome comparison of patients with trisomy 21 (Down), del7q11.23 (Williams-Beuren) and del22q11.2 (DiGeorge or Velo-Cardio-Facial) syndromes.

We report on a cross-syndrome comparison of hand, foot, eye and ear laterality in three groups of individuals with different genetic disorders (trisomy 21, del7q11.23, and del22q11.2) to test the relationship between atypical laterality and intellectual disability. These groups were compared to a group of typically developing persons. Hand, foot, eye and ear laterality was assessed using item tasks, conducted twice, and Bishop's card-reaching test. Ordering of the mean IQ score for each of the three groups was as follows: trisomy 21 < del7q11.23 < del22q11.2. We observed the same ordering as for IQ, particularly in mixed handedness, degree of laterality, hand and foot consistency. The existence of a cognitive threshold, below which lateral preference is atypical, advocates for a causal link between cognition and laterality in those with low IQ although unknown other factors underlying both could determine this association.

Mouse models of cognitive disabilities in trisomy 21 (Down syndrome).

Trisomy 21 (TRS21), also referred to as Down syndrome, occurs once in every 800-1,000 live births. It is the consequence of an extra copy of HSA21 that causes an imbalanced gene dose effect. TRS21 is the first known genetic cause of cognitive disability. The syndrome is complex, and includes various cardiac, immune, and bone disorders. Most of these signs are highly variable in expression but cognitive disability is the most constant characteristic of persons with TRS21. The syntenies that exist between HSA21 and three mouse chromosomes (MMU10, MMU16, and MMU17) offer the opportunity for a genotype-phenotype correlation. We present here the segmental trisomies available in the mouse and we discuss their contribution to the brain and cognitive phenotypes of TRS21.

Brain pathways mediating the pro-aggressive effect of the steroid sulfatase (Sts) gene.

STS is the single enzyme that converts all steroid sulfates into their free steroid forms. Initiation of attack behavior against conspecific male mice appeared to be linked to Sts. Here we have confirmed the role of Sts through an association study with attack behavior. Previous studies indicated a positive correlation between the initiation of attack behavior and liver STS concentration levels in male mice, but this finding was not compatible with established knowledge of STS mechanisms. High STS concentrations induce low concentrations of sulfated steroids. Sulfated and un-sulfated steroids are GABA(A) receptor agonists and NMDA receptor positive allosteric modulators. This synaptic pattern of functioning can generate attack behavior and we have confirmed here that an injection of the sulfated steroid dehydroepiandrosterone sulfate (DHEA-S) increases attack behavior. To solve the paradox, we measured the transcription activity of the genes underlying the pathways involved in the hydrolysis of sulfated steroids and leading to the formation of un-conjugated steroids in the mouse brain. We observed that the genes monitoring the steroid biosynthesis pathways exhibited a transcription pattern resulting in an increased sulfotransferase activity in the attacking males that could counterbalance the de-sulfating activity of Sts in the attacking mice.

Specific grasp characteristics of children with trisomy 21.

Children with trisomy 21 display atypical manual skills that change to some extent during development. We examined grasp characteristics and their development in 35 children with trisomy 21, aged 4-18 years, who performed simple manual tasks (two manual tasks of the Movement Assessment Battery for Children, and grasping of five wooden blocks whose size was determined by their hand size). The age-matched comparison group included 35 typically developing children. Children with trisomy 21 were found to use fewer fingers than children in the comparison group in each task. They also used specific grasps and tended to extend fingers that were not involved in the grip. While some specific grasp characteristics of children with trisomy 21 decreased with age, other did not, and remained present throughout development. The perceptual-motor development of children with trisomy 21 should be analyzed in terms of atypical development rather than developmental delay.

Postnatal Tshz3 Deletion Drives Altered Corticostriatal Function and Autism Spectrum Disorder-like Behavior.

BACKGROUND: Heterozygous deletion of the TSHZ3 gene, encoding for the teashirt zinc-finger homeobox family member 3 (TSHZ3) transcription factor that is highly expressed in cortical projection neurons (CPNs), has been linked to an autism spectrum disorder (ASD) syndrome. Similarly, mice with Tshz3 haploinsufficiency show ASD-like behavior, paralleled by molecular changes in CPNs and corticostriatal synaptic dysfunctions. Here, we aimed at gaining more insight into "when" and "where" TSHZ3 is required for the proper development of the brain, and its deficiency crucial for developing this ASD syndrome. METHODS: We generated and characterized a novel mouse model of conditional Tshz3 deletion, obtained by crossing Tshz3flox/flox with CaMKIIalpha-Cre mice, in which Tshz3 is deleted in CPNs from postnatal day 2 to 3 onward. We characterized these mice by a multilevel approach combining genetics, cell biology, electrophysiology, behavioral testing, and bioinformatics. RESULTS: These conditional Tshz3 knockout mice exhibit altered cortical expression of more than 1000 genes, ∼50% of which have their human orthologue involved in ASD, in particular genes encoding for glutamatergic synapse components. Consistently, we detected electrophysiological and synaptic changes in CPNs and impaired corticostriatal transmission and plasticity. Furthermore, these mice showed strong ASD-like behavioral deficits. CONCLUSIONS: Our study reveals a crucial postnatal role of TSHZ3 in the development and functioning of the corticostriatal circuitry and provides evidence that dysfunction in these circuits might be determinant for ASD pathogenesis. Our conditional Tshz3 knockout mouse constitutes a novel ASD model, opening the possibility for an early postnatal therapeutic window for the syndrome linked to TSHZ3 haploinsufficiency.

Hand preference and hand performance: cross-sectional developmental trends and family resemblance in degree of laterality.

The first aim of the study was to compare developmental trends in the degree of laterality (independent of direction) observed in two handedness tasks. The second aim was to assess family resemblance in the degree of laterality using the same two tasks. The sample was comprised of 186 left-handers and 302 right-handers aged from 6 to 66. Some of the sample were members of the same families. Bishop's card-reaching task was used to assess hand preference, and Annett's peg-moving task to assess manual performance. For the card-reaching task, children aged 7 to 10/11 recorded more midline crossings than the other age groups (both younger and older). No general age-related trend was observed for the Annett pegboard. For the card-reaching task, family resemblance was very low and not significant. The degree of laterality, assessed with the peg-moving task, showed a small but significant resemblance in father-offspring pairs (sons and daughters). Putative involvement of a maternally suppressed gene on chromosome 2p12 and of the androgen receptor was discussed.

Measuring Preweaning Sensorial and Motor Development in the Mouse.

The immaturity at birth and the slowness of ontogenic processes in mice provide the opportunity to measure rates of development. We describe here 18 measures covering the sensorial and motor onset from birth to weaning. The measures are non-invasive, making a follow-up strategy possible. The first basic protocol indicates how to produce mice with known conceptional or chronological age, as the control of the age is a prerequisite to compare rates of development in groups of mice. The second basic protocol describes a set of methods for identifying the pups during a follow-up study. A third basic protocol describes testing newborn mice for the appearance of sensorial and motor abilities in a follow-up design. Taken together, the three protocols make possible the validation of potential murine models of interest for understanding human developmental disorders. © 2018 by John Wiley & Sons, Inc.

Relationships Between Self-Injurious Behaviors, Pain Reactivity, and ß-Endorphin in Children and Adolescents With Autism.

OBJECTIVE: Autism and certain associated behaviors including self-injurious behaviors (SIB) and atypical pain reactivity have been hypothesized to result from excessive opioid activity. The objective of this study was to examine the relationships between SIB, pain reactivity, and ß-endorphin levels in autism. METHODS: Study participants were recruited between 2007 and 2012 from day care centers and included 74 children and adolescents diagnosed with autism (according to DSM-IV-TR, ICD-10, and CFTMEA) and intellectual disability. Behavioral pain reactivity and SIB were assessed in 3 observational situations (parents at home, 2 caregivers at day care center, a nurse and child psychiatrist during blood drawing) using validated quantitative and qualitative scales. Plasma ß-endorphin concentrations were measured in 57 participants using 2 different immunoassay methods. RESULTS: A high proportion of individuals with autism displayed SIB (50.0% and 70.3% according to parental and caregiver observation, respectively). The most frequent types of SIB were head banging and hand biting. An absence or decrease of overall behavioral pain reactivity was observed in 68.6% and 34.2% of individuals with autism according to parental and caregiver observation, respectively. Those individuals with hyporeactivity to daily life accidental painful stimuli displayed higher rates of self-biting (P < .01, parental evaluation). No significant correlations were observed between ß-endorphin level and SIB or pain reactivity assessed in any of the 3 observational situations. CONCLUSIONS: The absence of any observed relationships between ß-endorphin level and SIB or pain reactivity and the conflicting results of prior opioid studies in autism tend to undermine support for the opioid theory of autism. New perspectives are discussed regarding the relationships found in this study between SIB and hyporeactivity to pain.

Nonequivalence of computerized and paper-and-pencil versions of Trail Making Test.

A computerized version of the Trail Making Test, an adaptation of the classical paper-and-pencil form, was compared with the paper-and-pencil form. The testee must connect targets on the screen with the cursor using the mouse instead of a sheet of paper and a pen. The participants were 68 healthy adolescents and young adults. The comparison of scores on the two versions showed that they cannot be considered equivalent; the difference between the two parts of the test (Parts A and B) was greater in the paper-and-pencil version; correlations between the two versions of Part A and of Part B were significant, but too low to consider the two versions parallel. Both versions were accepted by participants. As expected, mean scores were different in Parts A and B in both versions and magnitude of differences was large.

Implicit theories concerning the intelligence of individuals with Down syndrome.

Studies over the past three decades have shown that learning difficulties are not only determined by neurological disorders, but also by motivational and/or socio-cognitive factors Among these factors, implicit theories of intelligence (also referred to as conceptions, mindsets or beliefs about intelligence) are key elements. The belief that intelligence is fixed (entity theory), as opposed to malleable (incremental theory), is generally associated with negative teaching practices and poorer student outcomes, yet beliefs about the intelligence of individuals with intellectual disabilities have not received much attention. We propose the first study on conceptions of intelligence of persons with intellectual disabilities, here people with Down syndrome. Participants were 55 professionally qualified people working with individuals with intellectual disabilities and 81 adults from the community. We compared what both groups of participants believe about intelligence of typical people and what they believe about the intelligence of individuals with Down syndrome. We also investigated implicit theories of intelligence as predictors of explicit judgments about intelligence and implicit attitudes toward people with Down syndrome. Whatever the work experience in the field of intellectual disability, implicit theories of intelligence were found to be less incremental when considering people with Down syndrome than when considering typical people; and the stronger the belief in entity theory, the more negative (and less positive) the judgments expressed explicitly. Implicit theories of intelligence were also found to be predictors of negative implicit attitude but only in adults from the community. These findings offer prospects for improving practices by people working in the field of intellectual disability. They might interest a wide range of people caring for people with intellectual disabilities, such as teachers, but also other professional caregivers, and other scientists focusing on intellectual disabilities or social cognition.

TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons.

TSHZ3, which encodes a zinc-finger transcription factor, was recently positioned as a hub gene in a module of the 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 19q12-q13.11, which includes autism spectrum disorder (ASD). In Tshz3-null mice, differentially expressed genes include layer-specific markers of cerebral cortical projection neurons (CPNs), and the human orthologs of these genes are strongly associated with ASD. Furthermore, mice heterozygous for Tshz3 show functional changes at synapses established by CPNs and exhibit core ASD-like behavioral abnormalities. These findings highlight essential roles for Tshz3 in CPN development and function, whose alterations can account for ASD in the newly defined TSHZ3 deletion syndrome.

Evaluation of a dermatoglyphic index to detect placental type variation in MZ twins.

A dermatoglyphic index, which was previously used retrospectively to assess relationships between placental type in MZ twins with other variables, was tested for verification in two new separate samples of twins of known placental type. In both a French twin sample (19 monochorionic and 24 dichorionic) and the U.S. twin sample (49 monochorionic and 22 dichorionic), dermatoglyphic index scores were higher in monochorionic than dichorionic pairs. The difference in scores attained statistical significance when the two new samples were pooled. It is concluded that although the index cannot be used retrospectively to classify an individual MZ twin pair, an association of the placental type dermatoglyphic score with another variable in a group of MZ twins without any placentation information provides support for continuing to investigate prenatal effects on the associated variable. Am. J. Hum. Biol. 9:609-615, 1997. © 1997 Wiley-Liss, Inc.

Misleading face-based judgment of cognitive level in intellectual disability: the case of trisomy 21 (Down syndrome).

People spontaneously use faces to make inferences about other's personality traits or abilities, which generally lead to invalid conclusions. Here, we show first evidence that perceived variations in the facial appearance of 20 children with trisomy 21 (t21) influence how they are perceived in terms of intelligence (or intellectual disability), the more "trisomic" faces being rated as less intelligent (or more intellectually disabled). Despite high degrees of inter-rater agreement (80 raters), these inferences were unrelated to individuals' actual test scores which were also unrelated to perceived facial appearance. All these findings indicate that social inferences about intelligence based on facial appearance are unreliable even in groups characterized by a genetic disorder such as t21.