Loren A. Martin

Consensus Paper: Pathological Role of the Cerebellum in Autism

There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin-related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene–environment interactions, therapeutics in autism, and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia, and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation.

Repetitive behavior and increased activity in mice with Purkinje cell loss: a model for understanding the role of cerebellar pathology in autism

Repetitive behaviors and hyperactivity are common features of developmental disorders, including autism. Neuropathology of the cerebellum is also a frequent occurrence in autism and other developmental disorders. Recent studies have indicated that cerebellar pathology may play a causal role in the generation of repetitive and hyperactive behaviors. In this study, we examined the relationship between cerebellar pathology and these behaviors in a mouse model of Purkinje cell loss. Specifically, we made aggregation chimeras between Lc/+ mutant embryos and +/+ embryos. Lc/+ mice lose 100% of their Purkinje cells postnatally due to a cell‐intrinsic gain‐of‐function mutation. Through our histological examination, we demonstrated that Lc/+↔+/+ chimeric mice have Purkinje cells ranging from zero to normal numbers. Our analysis of these chimeric cerebella confirmed previous studies on Purkinje cell lineage. The results of both open‐field activity and hole‐board exploration testing indicated negative relationships between Purkinje cell number and measures of activity and investigatory nose‐poking. Additionally, in a progressive‐ratio operant paradigm, we found that Lc/+ mice lever‐pressed significantly less than +/+ controls, which led to significantly lower breakpoints in this group. In contrast, chimeric mice lever‐pressed significantly more than controls and this repetitive lever‐pressing behavior was significantly and negatively correlated with total Purkinje cell numbers. Although the performance of Lc/+ mice is probably related to their motor deficits, the significant relationships between Purkinje cell number and repetitive lever‐pressing behavior as well as open‐field activity measures provide support for a role of cerebellar pathology in generating repetitive behavior and increased activity in chimeric mice.

The cerebellum and spatial ability: dissection of motor and cognitive components with a mouse model system

The cerebellum has recently been linked to spatial navigation, as indicated by the inferior performance of cerebellar mutant or cerebellar lesioned animals in the water maze. The inability to dissociate motor from cognitive deficits in the impaired water maze performance has been a confounding variable in previous studies, however. In this study, we sought to define clearly the role of the cerebellar system in spatial navigation outside of motor control by creating a mouse model of Purkinje cell loss with intact motor ability, and testing these mice in the water maze. To this end, we made aggregation chimeras between Lc/+ mice, which lose all Purkinje cells postnatally, and +/+ control mice. Lc/+ mice are ataxic and show impaired rotor‐rod performance. By contrast, we show that Lc/+ ⇆ +/+ chimeras above a threshold of Purkinje cell loss show no outward signs of motor impairment and demonstrated normal rotor‐rod ability. In the water maze, we found that Lc/+ mice showed impaired performance in the place, cue and platform removal tasks, whereas Lc/+⇆+/+ chimeras performed similarly to controls in all tasks. We found that the impaired performance in the water maze of Lc/+ mice resulted from both motor as well as cognitive impairment that could be separated from one another by statistical means. In addition, through the analysis of individual chimeric mice, the relationships between these deficits and the total number of Purkinje cells were determined and a specific role for Purkinje cells in search strategy was identified.

Validation of operant social motivation paradigms using BTBR T+tf/J and C57BL/6J inbred mouse strains.

As purported causal factors are identified for autism spectrum disorder (ASD), new assays are needed to better phenotype animal models designed to explore these factors. With recent evidence suggesting that deficits in social motivation are at the core of ASD behavior, the development of quantitative measures of social motivation is particularly important. The goal of our study was to develop and validate novel assays to quantitatively measure social motivation in mice.

The Effects of Birth Order and Birth Interval on the Phenotypic Expression of Autism Spectrum Disorder

A rise in the prevalence of diagnosed cases of autism spectrum disorder (ASD) has been reported in several studies in recent years. While this rise in ASD prevalence is at least partially related to increased awareness and broadened diagnostic criteria, the role of environmental factors cannot be ruled out, especially considering that the cause of most cases of ASD remains unknown. The study of families with multiple affected children can provide clues about ASD etiology. While the majority of research on ASD multiplex families has focused on identifying genetic anomalies that may underlie the disorder, the study of symptom severity across ASD birth order may provide evidence for environmental factors in ASD. We compared social and cognitive measures of behavior between over 300 first and second affected siblings within multiplex autism families obtained from the Autism Genetic Resource Exchange dataset. Measures included nonverbal IQ assessed with the Ravens Colored Progressive Matrices, verbal IQ assessed with the Peabody Picture Vocabulary Test, and autism severity assessed with the Social Responsiveness Scale (SRS), an instrument established as a quantitative measure of autism. The results indicated that females were more severely impacted by ASD than males, especially first affected siblings. When first and second affected siblings were compared, significant declines in nonverbal and verbal IQ scores were observed. In addition, SRS results demonstrated a significant increase in autism severity between first and second affected siblings consistent with an overall decline in function as indicated by the IQ data. These results remained significant after controlling for the age and sex of the siblings. Surprisingly, the SRS scores were found to only be significant when the age difference between siblings was less than 2 years. These results suggest that some cases of ASD are influenced by a dosage effect involving unknown epigenetic, environmental, and/or immunological factors.

Quantifying Social Motivation in Mice Using Operant Conditioning.

In this protocol, social motivation is measured in mice through a pair of operant conditioning paradigms. To conduct the experiments, two-chambered shuttle boxes were equipped with two operant levers (left and right) and a food receptacle in one chamber, which was then divided from the second chamber by an automated guillotine door covered by a wire grid. Different stimulus mice, rotated across testing days, served as a social stimulus behind the wire grid, and were only visible following the opening of the guillotine door. Test mice were trained to lever press in order to open the door and gain access to the stimulus partner for 15 sec. The number of lever presses required to obtain the social reward progressively increased on a fixed schedule of 3. Testing sessions ended after test mice stopped lever pressing for 5 consecutive minutes. The last reinforced ratio or breakpoint can be used as a quantitative measure of social motivation. For the second paradigm, test mice were trained to discriminate between left and right lever presses in order to obtain either a food reward or the social reward. Mice were rewarded for every 3 presses of each respective lever. The number of food and social rewards can be compared as a measurement of the value placed upon each reward. The ratio of each reward type can also be compared between mouse strains and the change in this ratio can be monitored within testing sessions to measure satiation with a given reward type. Both of these operant conditioning paradigms are highly useful for the quantification of social motivation in mouse models of autism and other disorders of social behavior.

Consistent hypersocial behavior in mice carrying a deletion of Gtf2i but no evidence of hyposocial behavior with Gtf2i duplication: Implications for Williams-Beuren syndrome and autism spectrum disorder

Williams–Beuren syndrome (WBS) is a developmental disorder caused by hemizygous deletion of human chromosome 7q11.23. Hypersocial behavior is one symptom of WBS and contrasts with hyposociality observed in autism spectrum disorder (ASD). Interestingly, duplications of 7q11.23 have been associated with ASD. The social phenotype of WBS has been linked to GTF2I or general transcription factor IIi (TFII‐I). Duplication of GTF2I has also been associated with ASD.

Slowing Down Time: An Exploration of Personal Life Extension Desirability as it Relates to Religiosity and Specific Religious Beliefs

As medical technology continues increasing the possibility of living a longer life, the public’s valuing of these developments must be considered. This study examines attitudes toward extending the human life span within a student population at a Christian university. Religious factors were hypothesized to affect life extension desirability. Scores on measures of willingness to defer to God’s will, meaning derived from religion, positive afterlife beliefs, and intrinsic religiosity were significantly and inversely related to life extension desirability. Implications of these findings are discussed, including encouraging medical practitioners to respect decision-making processes of religious persons who may find life extension interventions undesirable.

Quantitative autistic traits are transmitted intergenerationally and increase risk for autism spectrum disorders

ABSTRACT FROM : Lyall K, Constantino JN, Weisskopf MG, et al . Parental social responsiveness and risk of autism spectrum disorder in offspring. JAMA Psychiatry 2014;71:936–42. The heritability of autism spectrum disorders (ASD) has previously been suggested by studies on twin and other sibling populations.1 ,2 However, ASD may manifest subclinically in some individuals complicating the study of genetic risk factors. The ability to accurately quantify subclinical ASD, or quantitative autistic traits (QAT), is thus critical to the study of ASD heritability. Several previous studies have suggested that QAT are also heritable.3 ,4 This study provides further evidence of the intergenerational transmission of QAT. Participants were solicited from a longitudinal cohort of 116 430 nurses who are part of the Nurses’ Health Study II (NHS II). Cases were index children with …