The cerebellum contains the largest number of neurons and synapses of any structure in the central nervous system. The concept that the cerebellum is solely involved in fine motor function has become outdated; substantial evidence has accumulated linking the cerebellum with higher cognitive functions including language. Cerebellar deficits have been implicated in autism for more than two decades. The computational power of the cerebellum is essential for many, if not most of the processes that are perturbed in autism including language and communication, social interactions, stereotyped behavior, motor activity and motor coordination, and higher cognitive functions. The link between autism and cerebellar dysfunction should not be surprising to those who study its cellular, physiological, and functional properties. Postmortem studies have revealed neuropathological abnormalities in cerebellar cellular architecture while studies on mouse lines with cell loss or mutations in single genes restricted to cerebellar Purkinje cells have also strongly implicated this brain structure in contributing to the autistic phenotype. This connection has been further substantiated by studies investigating brain damage in humans restricted to the cerebellum. In this review, we summarize advances in research on idiopathic autism and three genetic forms of autism that highlight the key roles that the cerebellum plays in this spectrum of neurodevelopmental disorders.

/pdf/autism-spectrum-disorders-and-neuropathology-of-the-360dsxqrvu.pdf

Autism spectrum disorders and neuropathology of the cerebellum

While the insulin receptor (IR) was found in the CNS decades ago, the brain was long considered to be an insulin-insensitive organ. This view is currently revisited, given emerging evidence of critical roles of IR-mediated signaling in development, neuroprotection, metabolism, and plasticity in the brain. These diverse cellular and physiological IR activities are distinct from metabolic IR functions in peripheral tissues, thus highlighting region specificity of IR properties. This particularly concerns the fact that two IR isoforms, A and B, are predominantly expressed in either the brain or peripheral tissues, respectively, and neurons express exclusively IR-A. Intriguingly, in comparison with IR-B, IR-A displays high binding affinity and is also activated by low concentrations of insulin-like growth factor-2 (IGF-2), a regulator of neuronal plasticity, whose dysregulation is associated with neuropathologic processes. Deficiencies in IR activation, insulin availability, and downstream IR-related mechanisms may result in aberrant IR-mediated functions and, subsequently, a broad range of brain disorders, including neurodevelopmental syndromes, neoplasms, neurodegenerative conditions, and depression. Here, we discuss findings on the brain-specific features of IR-mediated signaling with focus on mechanisms of primary receptor activation and their roles in the neuropathology. We aimed to uncover the remaining gaps in current knowledge on IR physiology and highlight new therapies targeting IR, such as IR sensitizers.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cns.12866

Insulin receptor in the brain: Mechanisms of activation and the role in the CNS pathology and treatment

Sensory abnormalities are commonly recognized as diagnostic criteria in autism spectrum disorder (ASD), as reported in the last edition of the Diagnostic and Statistical Manual of Mental Disorder (DSM-V). About 90% of ASD individuals have atypical sensory experiences, described as both hyper- and hypo-reactivity, with abnormal responses to tactile stimulation representing a very frequent finding. In this review, we will address the neurobiological bases of sensory processing in ASD, with a specific focus of tactile sensitivity. In the first part, we will review the most relevant sensory abnormalities detected in ASD, and then focus on tactile processing deficits through the discussion of recent clinical and experimental studies. In the search for the neurobiological bases of ASD, several mouse models have been generated with knockout and humanized knockin mutations in many ASD-associated genes. Here, we will therefore give a brief overview of the anatomical structure of the mouse somatosensory system, and describe the somatosensory abnormalities so far reported in different mouse models of ASD. Understanding the neurobiological bases of sensory processing in ASD mouse models may represent an opportunity for a better comprehension of the mechanisms underlying sensory abnormalities, and for the development of novel effective therapeutic strategies.

Sensory Abnormalities in Autism Spectrum Disorders: A Focus on the Tactile Domain, From Genetic Mouse Models to the Clinic.

The development of an autistic brain is a highly complex process as evident from the involvement of various genetic and non-genetic factors in the etiology of the autism spectrum disorder (ASD). Despite being a multifactorial neurodevelopmental disorder, autistic patients display a few key characteristics, such as the impaired social interactions and elevated repetitive behaviors, suggesting the perturbation of specific neuronal circuits resulted from abnormal signaling pathways during brain development in ASD. A comprehensive review for autistic signaling mechanisms and interactions may provide a better understanding of ASD etiology and treatment. Recent studies on genetic models and ASD patients with several different mutated genes revealed the dysregulation of several key signaling pathways, such as WNT, BMP, SHH, and retinoic acid (RA) signaling. Although no direct evidence of dysfunctional FGF or TGF-β signaling in ASD has been reported so far, a few examples of indirect evidence can be found. This review article summarizes how various genetic and non-genetic factors which have been reported contributing to ASD interact with WNT, BMP/TGF-β, SHH, FGF, and RA signaling pathways. The autism-associated gene ubiquitin-protein ligase E3A (UBE3A) has been reported to influence WNT, BMP, and RA signaling pathways, suggesting crosstalk between various signaling pathways during autistic brain development. Finally, the article comments on what further studies could be performed to gain deeper insights into the understanding of perturbed signaling pathways in the etiology of ASD. The understanding of mechanisms behind various signaling pathways in the etiology of ASD may help to facilitate the identification of potential therapeutic targets and design of new treatment methods.

/pdf/impaired-neurodevelopmental-pathways-in-autism-spectrum-1ed9n9a806.pdf

Impaired neurodevelopmental pathways in autism spectrum disorder: a review of signaling mechanisms and crosstalk.

The cerebellum has been repeatedly implicated in gene expression, rodent model and post-mortem studies of autism spectrum disorder (ASD). How cellular and molecular anomalies of the cerebellum relate to clinical manifestations of ASD remains unclear. Separate circuits of the cerebellum control different sensorimotor behaviors, such as maintaining balance, walking, making eye movements, reaching and grasping. Each of these behaviors has been found to be impaired in ASD, suggesting that multiple distinct circuits of the cerebellum may be involved in the pathogenesis of patients’ sensorimotor impairments. We will review evidence that the development of these circuits is disrupted in individuals with ASD and that their study may help elucidate the pathophysiology of sensorimotor deficits and core symptoms of the disorder. Preclinical studies of monogenetic conditions associated with ASD also have identified selective defects of the cerebellum and documented behavioral rescues when the cerebellum is targeted. Based on these findings, we propose that cerebellar circuits may prove to be promising targets for therapeutic development aimed at rescuing sensorimotor and other clinical symptoms of different forms of ASD.

https://kuscholarworks.ku.edu/bitstream/handle/1808/20068/mosconi_cerebellar.pdf;sequence=1

The role of cerebellar circuitry alterations in the pathophysiology of autism spectrum disorders

REarranged during Transfection (RET) is a mammalian tyrosine kinase receptor involved in the signal transduction pathways during early embryonic kidney and enteric nervous system development. Activation of RET is mediated by one of the membrane associated co-receptors GFRal-4 and one of the four GFL family ligands. Following ligand binding, RET undergoes autophosphorylation followed by downstream activation of additional cell signaling proteins. However, less is understood about the downregulation patterns of RET and of naturally occurring RET mutants and laboratory modified forms of RET. In this study, the role of the cytoplasmic domain in receptor processing and protein degradation was analyzed. In addition, protein stability rates of tyrosine autophosphorylation mutants and kinase inactive RET mutants were analyzed and compared to wild-type RET. Protein stability was assessed from 0-16 hr. The wildtype RET receptor displayed an overall decrease in the concentration of the glycosylated form, suggesting internalization of the receptor. Decrease in the membrane receptor is not observed in either the autophosphorylation mutant or the kinase inactive RET mutant. Results suggest that mutations associated with ihe intracellular domain of the receptor impede its protein modification and signaling to the membrane and further delays internalization and down-regulation. Down Regulation patterns of the Mutated RET Receptor Tyrosine Kinase

Down Regulation Patterns of the Mutated RET Receptor Tyrosine Kinase

Background 
Previous genetic studies demonstrated association between the transcription factor ENGRAILED2 (EN2) and Autism Spectrum Disorder (ASD) Subsequent molecular analysis determined that the EN2 ASD-associated haplotype (rs1861972-rs1861973 A-C) functions as a transcriptional activator to increase gene expression EN2 is flanked by 5 genes, SEROTONIN RECEPTOR5A (HTR5A), INSULIN INDUCED GENE1 (INSIG1), CANOPY1 HOMOLOG (CNPY1), RNA BINDING MOTIF PROTEIN33 (RBM33), and SONIC HEDGEHOG (SHH) These flanking genes are co-expressed with EN2 during development and coordinate similar developmental processes To investigate if mRNA levels for these genes are altered in individuals with autism, post-mortem analysis was performed


Methods 
qRT-PCR quantified mRNA levels for EN2 and the 5 flanking genes in 78 post-mortem cerebellar samples mRNA levels were correlated with both affection status and rs1861972-rs1861973 genotype Molecular analysis investigated whether EN2 regulates flanking gene expression


Results 
EN2 levels are increased in affected A-C/G-T individuals (p = 0077) Affected individuals also display a significant increase in SHH and a decrease in INSIG1 levels Rs1861972-rs1861973 genotype is correlated with significant increases for SHH (A-C/G-T) and CNPY1 (G-T/G-T) levels Human cell line over-expression and knock-down as well as mouse knock-out analysis are consistent with EN2 and SHH being co-regulated, which provides a possible mechanism for increased SHH post-mortem levels


Conclusions 
EN2 levels are increased in affected individuals with an A-C/G-T genotype, supporting EN2 as an ASD susceptibility gene SHH, CNPY1, and INSIG1 levels are also significantly altered depending upon affection status or rs1861972-rs1861973 genotype Increased EN2 levels likely contribute to elevated SHH expression observed in the post-mortem samples

Autism Associated Gene, ENGRAILED2, and Flanking Gene Levels Are Altered in Post-Mortem Cerebellum

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Down Regulation Patterns of the Mutated RET Receptor Tyrosine Kinase

Autism Associated Gene, ENGRAILED2, and Flanking Gene Levels Are Altered in Post-Mortem Cerebellum