Consensus Paper: Pathological Role of the Cerebellum in Autism

In the paper

“Individuals with AD show impairments in executive function, memory and language abilities [205].”

What the sources say

• Partly supported

  The Discussion reports impaired memory for complex visual and verbal material in children with autism, and the paper discusses possible difficulties involving the central executive. It does not establish a general impairment in language ability; it says the memory differences remained after accounting for language level. Its findings also concern children with autism, rather than individuals with AD generally. (LLM, conf=0.84)

  cites [205] Williams DL, Goldstein G, Minshew NJ. The profile of memory function in children with autism. Neuropsychology. 2006;20(1):21–9. sourceExperimental — accuracy not yet measured

In the paper

“Ca2+ is rapidly removed from the cytoplasm into the extracellular space by plasma membrane calcium ATPases (PMCAs); the ATP2B2 gene encodes for PMCA2, whose faster kinetic and broader Ca2+ affinity range makes this PMCA critical to synaptic function and plasticity especially in the dendritic spines of Purkinje cells and in parvalbumin-positive gabaergic interneurons [244–246].”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [244] Empson RM, Garside ML, Knöpfel T. Plasma membrane Ca2+ ATPase 2 contributes to short-term synapse plasticity at the parallel fiber to Purkinje neuron synapse. J Neurosci. 2007;27:3753–8. sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [245] Burette AC, Strehler EE, Weinberg RJ. “Fast” plasma membrane calcium pump PMCA2a concentrates in GABAergic terminals in the adult rat brain. J Comp Neurol. 2009;512:500–13. sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [246] Garside ML, Turner PR, Austen B, Strehler EE, Beesley PW, Empson RM. Molecular interactions of the plasma membrane calcium ATPase 2 at pre- and post-synaptic sites in rat cerebellum. Neuroscience. 2009;162:383–95. sourceExperimental — accuracy not yet measured

In the paper

“Mice prenatally exposed to the PAH benzo(a)pyrene display blunted MET gene expression and behavioral deficits in a novelty test [253].”

What the sources say

• Supported

  The Results report significantly reduced Met transcript expression in the cerebral cortex of prenatally B(a)P-exposed mouse offspring at the middle and high doses from postnatal days 1–7. The novel-object discrimination findings (Figure 5, reproduced in the Discussion) show a significant behavioral deficit in exposed offspring compared with controls. (LLM, conf=0.94)

  cites [253] Sheng L, Ding X, Ferguson M, McCallister M, Rhoades R, Maguire M, et al. Prenatal polycyclic aromatic hydrocarbon exposure leads to behavioral deficits and downregulation of receptor tyrosine kinase, MET. Toxicol Sci. 2010;118:625–34. source

In the paper

“Despite several detailed analyses of the vermis, our studies have been unable to identify any abnormalities of PC size or number in this region, thus failing to provide any microscopic cellular explanation for vermal hypoplasia as reported by cranial imaging studies [8].”

What the sources say

• Not checked yetcites [8] Courchesne E, Saitoh O, Yeung-Courchesne R, Press GA, Lincoln AJ, et al. Abnormality of cerebellar vermian lobules VI and VII in patients with infantile autism: identification of hypoplastic and hyperplastic subgroups by MR imaging. AJR. 1994;162:123–30. source

In the paper

“Reduced levels of complexes III and V in the cerebellum, of complex I in the frontal cortex, and of complexes II, III, and V in the temporal cortex were observed in children with autism as compared to age-matched control subjects [103].”

What the sources say

• Not checked yetcites [103] Chauhan A, Gu F, Essa MM, Wegiel J, Kaur K, Brown WT, et al. Brain region-specific deficit in mitochondrial electron transport chain complexes in children with autism. J Neurochem. 2011;117:209–20. source

In the paper

“Our studies of different brain regions showed that oxidative stress differentially affects selective brain regions, i.e., cerebellum, temporal and frontal cortices, in autism [103–105, 107]. Increased oxidative stress and mitochondrial abnormalities were not observed in the parietal and occipital cortices in autism [103–105, 107].”

What the sources say

• Not checked yetcites [103] Chauhan A, Gu F, Essa MM, Wegiel J, Kaur K, Brown WT, et al. Brain region-specific deficit in mitochondrial electron transport chain complexes in children with autism. J Neurochem. 2011;117:209–20. source
• Not checked yetcites [104] Muthaiyah B, Essa MM, Chauhan V, Brown WT, Wegiel J, Chauhan A. Increased lipid peroxidation in cerebellum and temporal cortex of brain in autism. J Neurochem. 2009;108 Suppl 1:73.
• Not checked yetcites [105] Chauhan A, Audhya T, Chauhan V. Increased DNA oxidation in the cerebellum, frontal and temporal cortex of brain in autism. Transactions of the American Society for Neurochemistry. Windermere: American Society for Neurochemistry; 2011. p. 81.
• Not checked yetcites [107] Chauhan A, Essa MM, Muthaiyah B, Brown WT,Wegiel J, Chauhan V. Increased protein oxidation in cerebellum, frontal and temporal cortex in autism. International Meeting for Autism Research (Abstract), May 2010.

In the paper

“Whitney et al. [6] has suggested that the presence of reduced numbers of PCs in the brains of autistic individuals may not be present in all cases. In three of the six brains of autistic individuals, the number of PCs closely approximated that of the controls.”

What the sources say

• Not checked yetcites [6] Whitney ER, Kemper TL, Bauman ML, Rosene DL, Blatt GJ. Cerebellar Purkinje cells are reduced in a subpopulation of autistic brains: a stereological experiment using calbindin-D28k. Cerebellum. 2008;7(3):406–16. source

In the paper

“Autism is a clinically complex and heterogeneous disorder. The core features include delayed and disordered language, impaired social interaction, isolated areas of interest, and an insistence on sameness [1].”

What the sources say

• Not checked yetcites [1] American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed (DSM-4). Washington, DC: APA; 1994.

In the paper

“Currently, the cause of autism remains poorly defined but both genetic and environmental factors have been implicated [2].”

What the sources say

• Not checked yetcites [2] Wassink TH, Brzustowicz LM, Bartlett CW, Szatmari P. The search for autism disease genes. Ment Retard Dev Disabil Res Rev. 2004;10:272–83. source

In the paper

“Gaze linked to cerebellar function [23] is characteristically atypical in individuals with AD and the observation of subtle oculomotor alterations suggests abnormalities in cortico-cerebellar connectivity [24, 25].”

What the sources say

• Not checked yetcites [23] Brettler SC, Fuchs AF, Ling L. Discharge patterns of cerebellar output neurons in the caudal fastigial nucleus during head-free gaze shifts in primates. Ann NY Acad Sci. 2003;1004:61–8. source
• Not checked yetcites [24] Takarae Y, Minshew NJ, Luna B, Sweeney JA. Oculomotor abnormalities parallel cerebellar histopathology in autism. J Neurol Neurosurg Psychiatry. 2004;75(9):1359–61. source
• Not checked yetcites [25] Nowinski CV, Minshew NJ, Luna B, Takarae Y, Sweeney JA. Oculomotor studies of cerebellar function in autism. Psychiatry Res. 2005;137(1–2):11–9. source

In the paper

“It is known that the cerebellum connects with many cortical and subcortical structures in the cerebral hemispheres and acts as a modulator for many of the cognitive, language, motor, sensory and emotional functions associated with these regions [18].”

What the sources say

• Not checked yetcites [18] Schmahmann J. The cerebellum and cognition. International review of neurobiology, vol. 41. San Diego: Academic; 1997.

In the paper

“All of the autistic cases over the age of 21 years showed small pale neurons that were significantly decreased in number, whereas in all of the childhood cases, ages 5–13 years, the neurons in these same nuclear groups were unusually large and plentiful in numbers [14].”

What the sources say

• Not checked yetcites [14] Kemper TL, Bauman ML. Neuropathology of infantile autism. J Neuropath Exp Neurol. 1998;57:645–52. source

In the paper

“These findings support the concept that autism is a disorder of prenatal onset with neurobiological processes that extend into the postnatal period.”

In the paper

“These observations, in conjunction with similar findings in the nucleus of the Diagonal Band of Broca in the septum and in the inferior olivary nuclei, combined with observations of overgrowth of brain volume early in life [15, 16] and a more recent report of reduced cortical thickness with age [17], suggests that the underlying neuropathology of autism may be associated with an ongoing postnatal”

What the sources say

• Not checked yetcites [15] Hazlett HC, Poe M, Gerig G, Smith RG, Provenzale J, Ross A, et al. Magnetic resonance imaging and head circumference study of brain size in autism: birth through age 2 years. Arch Gen Psychiatry. 2005;62:11366–76. source
• Not checked yetcites [16] Lainhart JE, Bigler ED, Bocian M, Coon H, Dinh E, Dawson G, et al. Head circumference and height in autism: a study by the collaborative program of excellence in autism. Am J Med Genet A. 2006;140:2257–74. source
• Not checked yetcites [17] Hardan AY, Libove RA, Keshavan MS, Melhem NM, Minshew NJ. A preliminary longitudinal magnetic resonance imaging study of brain volume and cortical thickness in autism. Biol Psychiatry. 2009;66:313–5. source

In the paper

“For instance, the posterior vermis may have an important role in facilitating language function [27] which, although heterogeneous in AD, is a core impairment [28].”

What the sources say

• Not checked yetcites [27] Ackermann H, Wildgruber D, Daum I, Grodd W. Does the cerebellum contribute to cognitive aspects of speech production? A functional magnetic resonance imaging (fMRI) study in humans. Neurosci Lett. 1998;247(2–3):187–90. source
• Not checked yetcites [28] Tager-Flusberg H, Caronna E. Language disorders: autism and other pervasive developmental disorders. Pediatr Clin North Am. 2007;54(3):469–81. source

In the paper

“AD genetic architecture is complex, with variants of any individual locus present in only 1–2% of patients, and collectively all known genetic causes accounting for just 15% of cases [55].”

What the sources say

• Not checked yetcites [55] Schaaf CP, Zoghbi HY. Solving the autism puzzle a few pieces at a time. Neuron. 2011;70(5):806–8. source

In the paper

“For example, ~30% of patients with Fragile X Syndrome (FXS), the most common inherited cause of intellectual disability, are also diagnosed with AD. FXS is also one of the most common genetic causes of AD with >2% of AD patients co-diagnosed with FXS (http://www.fragilex.org).”

What the sources say

• Not checked yetcites http://www.fragilex.org

In the paper

“Thus, vermal hypoplasia, particularly lobules VI-VII, may be associated with AD but the specificity of this relationship is not well established and there is heterogeneity within AD.”

What the sources say

• Not checked yetcites [32] Scott JA, Schumann CM, Goodlin-Jones BL, Amaral DG. A comprehensive volumetric analysis of the cerebellum in children and adolescents with autism spectrum disorder. Autism Res. 2009;2(5):246–57. source
• Not checked yetcites [34] Courchesne E, Saitoh O, Townsend J, Yeung-Courchesne R, Press G, Lincoln A, et al. Cerebellar hypoplasia and hyperplasia in infantile autism. Lancet. 1994;343:63–4. source

In the paper

“Acquired cerebellar lesions involving the posterior lobe of the vermis, part of a reciprocal anatomical network with the anterior limbic system, have been associated with mild cognitive impairment, deficits of executive function, expressive language impairment, and affective blunting or disinhibition [31], all behaviors recognized in AD.”

What the sources say

• Not checked yetcites [31] Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain. 1998;121(4):561–79. source

In the paper

“Approximately 40% of TS patients are co-diagnosed with AD, and those with cerebellar lesions have more severe AD features than those with lesions restricted to other brain regions [60].”

What the sources say

• Not checked yetcites [60] Eluvathingal TJ, Behen ME, Chugani HT, Janisse J, Bernardi B, Chakraborty P, et al. Cerebellar lesions in tuberous sclerosis complex: neurobehavioral and neuroimaging correlates. J Child Neurol. 2006;21(10):846–51. source

In the paper

“Cerebellar vermis hypoplasia has been noted in seven patients with 22q13DS, suggesting that SHANK3 may be involved in cerebellar development [61, 62].”

What the sources say

• Not checked yetcites [61] Moessner R, Marshall CR, Sutcliffe JS, Skaug J, Pinto D, Vincent J, et al. Contribution of SHANK3 mutations to autism spectrum disorder. Am J Hum Genet. 2007;81(6):1289–97. source
• Not checked yetcites [62] Philippe A, Boddaert N, Vaivre-Douret L, Robel L, Danon-Boileau L, Malan V, et al. Neurobehavioral profile and brain imaging study of the 22q13.3 deletion syndrome in childhood. Pediatrics. 2008;122(2):e376–82. source

In the paper

“Homozygous mutations in AHI1 were the first identified JS cause and common genetic variation in AHI1, represented by single nucleotide polymorphisms (SNPs), was subsequently found to be associated with non-syndromic AD [64].”

What the sources say

• Not checked yetcites [64] Alvarez Retuerto AI, Cantor RM, Gleeson JG, Ustaszewska A, Schackwitz WS, Pennacchio LA, et al. Association of common variants in the Joubert syndrome gene (AHI1) with autism. Hum Mol Genet. 2008;17(24):3887–96. source

In the paper

“Elevated plasma cytokine levels (IL-1β, IL-6, IL-12p40 and TNFα) [82–84], altered immunoglobulin levels [85, 86], elevated levels of complement proteins [87], and increased chemokine levels (CCL2, CCL5 and CCL11) [88] are reported in the plasma of young children with AD compared with matched typically developing children.”

What the sources say

• Not checked yetcites [82] Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah I, Van de Water J. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immun. 2011;25:40–5. source
• Not checked yetcites [83] Ashwood P, Anthony A, Torrente F, Wakefield AJ. Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory interleukin-10. J Clin Immunol. 2004;24:664–73. source
• Not checked yetcites [84] Ashwood P, Wakefield AJ. Immune activation of peripheral blood and mucosal CD3+ lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms. J Neuroimmunol. 2006;173:126–34. source
• Not checked yetcites [85] Heuer L, Ashwood P, Goines P, Krakowiak P, Hertz-Picciotto I, Hansen R, et al. Reduced levels of immunoglobulin in children with autism correlates with behavioral symptoms. Autism Research. 2008;1:275–83. source
• Not checked yetcites [86] Enstrom A, Krakowiak P, Onore C, Pessah IN, Hertz-Picciotto I, Hansen RL, et al. Increased IgG4 levels in children with autism disorder. Brain Behav Immun. 2009;23:389–95. source
• Not checked yetcites [87] Corbett BA, Kantor AB, Schulman H, Walker WL, Lit L, Ashwood P, et al. A proteomic study of serum from children with autism showing differential expression of apolipoproteins and complement proteins. Mol Psychiatry. 2007;12:292–306. source

In the paper

“Thus, although the number of individuals diagnosed with both ADs and cerebellar malformations is small, the consistent finding of patients with both phenotypes implicates the cerebellum in autism pathogenesis and suggests that individuals with cerebellar malformations represent an important subgroup of AD patients.”

In the paper

“AD is diagnosed in up to 40% of children with Joubert Syndrome (JS), which is defined by significant cerebellar vermis hypoplasia and a distinctive brainstem malformation.”

In the paper

“Compared with controls, brain tissue specimens from cerebellum, midfrontal and cingulate gyrus in AD show marked activation of microglia and astrocytes with the up-regulation of the cell surface major histocompatibility complex (MHC) molecule HLA-DR and, glial fibrillary acidic protein, respectively. Prominent monocyte and macrophage accumulation in the cerebellum is also detected.”

What the sources say

• Not checked yetcites [73] Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57(1):67–81. source

In the paper

“A decrease in GSH, an increase in its oxidized disulfide form (GSSG) and a decrease in the redox ratio of GSH/GSSG were observed in the cerebellum and temporal cortex of individuals with autism, suggesting a glutathione redox imbalance in autism [111].”

What the sources say

• Not checked yetcites [111] Chauhan A, Audhya T, Chauhan V. Brain region-specific glutathione redox imbalance and increased DNA oxidation in autism. J Neurochem. 2011;118(suppl 1):217.

In the paper

“Accumulating evidence suggests that a common feature in autism cases may be oxidative stress, the mechanism through which environmental factors exert their deleterious effects, which may be further exacerbated by the interaction of genetically susceptible alleles [96–100].”

What the sources say

• Not checked yetcites [96] Chauhan A, Chauhan V, Brown WT, editors. Autism: oxidative stress, inflammation and immune abnormalities. Boca Raton: CRC Press; 2009.
• Not checked yetcites [97] Deth R, Muratore C, Benzecry J, Power-Charnitsky VA, Waly M. How environmental and genetic factors combine to cause autism: a redox/methylation hypothesis. Neurotoxicology. 2008;29:190–201. source
• Not checked yetcites [98] Chauhan A, Chauhan V. Oxidative stress in autism. Pathophysiology. 2006;13:171–81. source
• Not checked yetcites [99] Kern JK, Jones AM. Evidence of toxicity, oxidative stress, and neuronal insult in autism. J Toxicol Environ Health B Crit Rev. 2006;9:485–99. source
• Not checked yetcites [100] Wells PG, McCallum GP, Chen CS, Henderson JT, Lee CJ, Perstin J, et al. Oxidative stress in developmental origins of disease: teratogenesis, neurodevelopmental deficits, and cancer. Toxicol Sci. 2009;108:4–18. source

In the paper

“Reeler heterozygous mice, which are haploinsufficient for reelin, exhibit decreased GAD 67 [138] and reduced GABAA and GABAB receptors in the whole brain and hippocampus, respectively [139].”

What the sources say

• Not checked yetcites [138] Nullmeier S, Panther P, Dobrowolny H, Frotscher M, Zhao S, Schwegler H, et al. Region-specific alteration of GABAergic markers in the brain of heterozygous reeler mice. Eur J Neurosci. 2011;33:689–98. source
• Not checked yetcites [139] Cremer CM, Lubke JH, Palomero-Gallagher N, Zilles K. Laminar distribution of neurotransmitter receptors in different reeler mouse brain regions. Brain Struct Funct. 2011;216:201–18. source

In the paper

“As a serine protease of the extracellular matrix, Reelin regulates proper lamination of neurons during embryonic development and helps in migration of neurons and maintenance of synaptic plasticity throughout life [135–137].”

What the sources say

• Not checked yetcites [135] Quattrocchi CC, Wannenes F, Persico AM, Ciafré SA, D’Arcangelo G, Farace MG, et al. Reelin is a serine protease of the extracellular matrix. J Biol Chem. 2002;277:303–9. source
• Not checked yetcites [136] Weeber EJ, Beffert U, Jones C, Christian JM, Forster E, Sweatt JD, et al. Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning. J Biol Chem. 2002;277:39944–52. source
• Not checked yetcites [137] Forster E, Tielsch A, Saum B, Weiss KH, Johanssen C, Graus-Porta D, et al. Reelin, Disabled 1, and beta 1 integrins are required for the formation of the radial glial scaffold in the hippocampus. Proc Natl Acad Sci. 2002;99:13178–83. source

In the paper

“FMRP, translated from the Fragile X mental retardation-1 (FMR1) gene, is an RNA-binding protein involved in post-transcriptional regulation of target RNAs [157] and binds approximately 4% of the mRNA expressed in the brain [158].”

What the sources say

• Not checked yetcites [157] De Rubeis S, Bagni C. Fragile X mental retardation protein control of neuronal mRNA metabolism: insights into mRNA stability. Mol Cell Neurosci. 2010;43:43–50. source
• Not checked yetcites [158] Bassell GJ, Warren ST. Fragile X Syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron. 2008;60:201–14. source

In the paper

“Glutamate is important in the acquisition of emotional behavior [149] and N-methyl-aspartic acid (NMDA)-glutamate receptors are responsible for long term potentiation [150], underlying learning and memory; two processes impaired in subjects with autism.”

What the sources say

• Not checked yetcites [149] Hoehn-Saric R, McLeod DR, Glowa JR. The effects NMDA receptor blockade on the acquisition of a conditioned emotional response. Biol Psychiatry. 1991;30:170–6. source
• Not checked yetcites [150] Lisman J. Long-term potentiation: outstanding questions and attempted synthesis. Philos Trans R Soc Lond B Biol Sci. 2003;358:829–42. source

In the paper

“Glutamate is the main excitatory neurotransmitter in the brain and it plays a key role during brain development by regulating multiple processes including neurogenesis, neuronal outgrowth, neuron survival, and synaptogenesis [148].”

What the sources say

• Not checked yetcites [148] Mattson MP. Glutamate and neurotrophic factors in neuronal plasticity and disease. Ann N Y Acad Sci. 2008;1144:97–112. source

In the paper

“Reelin binds to several protein receptors, including very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor 2 and α3β1 integrin [144–146].”

What the sources say

• Not checked yetcites [144] D’Arcangelo G, Homayouni R, Keshvara L, Rice DS, Sheldon M, Curran T. Reelin is a ligand for lipoprotein receptors. Neuron. 1999;24:471–9. source
• Not checked yetcites [145] Hiesberger T, Trommsdorff M, Howell BW, Goffinet A, Mumby MC, Cooper JA, et al. Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation. Neuron. 1999;24:481–9. source
• Not checked yetcites [146] Dulabon L, Olson EC, Taglienti MG, Eisenhuth S, McGrath B, Walsh CA, et al. Reelin binds alpha3beta1 integrin and inhibits neuronal migration. Neuron. 2000;27:33–44. source

In the paper

“Several studies have demonstrated abnormal reelin expression in autism and replicated these results; notably, polymorphisms of the RELN gene [140, 141], decreased Reelin mRNA in superior frontal cortex and cerebellum [89], and reduced Reelin expression in blood analyses [143].”

What the sources say

• Not checked yetcites [140] Kelemenova S, Schmidtova E, Ficek A, Celec P, Kubranska A, Ostatnikova D. Polymorphisms of candidate genes in Slovak autistic patients. Psychiatr Genet. 2010;20:137–9. source
• Not checked yetcites [141] Persico AM, D’Agruma L, Maiorano N, Totaro A, Militerni R, Bravaccio C, et al. Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Mol Psychiatry. 2001;6:150–9. source
• Not checked yetcites [89] Enstrom AM, Lit L, Onore CE, Gregg JP, Hansen R, Pessah IN, et al. Altered gene expression and function of peripheral blood natural killer cells in children with autism. Brain Behav Immun. 2009;23:124–33. source
• Not checked yetcites [143] Fatemi SH, Stary JM, Egan EA. Reduced blood levels of reelin as a vulnerability factor in pathophysiology of autistic disorder. Cell Mol Neurobiol. 2002;22:139–52. source

In the paper

“VLDLR is upregulated in the superior frontal cortex and cerebellum in adult patients with autism, while Dab-1 is significantly reduced in these areas [89], suggesting impaired signaling in the Reelin pathway.”

What the sources say

• Not checked yetcites [89] Enstrom AM, Lit L, Onore CE, Gregg JP, Hansen R, Pessah IN, et al. Altered gene expression and function of peripheral blood natural killer cells in children with autism. Brain Behav Immun. 2009;23:124–33. source

In the paper

“Mutations involving the fragile X mental retardation protein (FMRP) lead to Fragile X syndrome (FXS). Individuals with FXS and autism often share overlapping diagnoses [156].”

What the sources say

• Not checked yetcites [156] Demark JL, Feldman MA, Holden JJ. Behavioral relationship between autism and fragile X syndrome. Am J Ment Retard. 2003;108:314–26. source

In the paper

“In addition, FMRP has been demonstrated to be significantly reduced in the cerebellum and frontal cortex of autistic subjects, while mGluR5 is elevated in the brains of children with autism.”

In the paper

“OTR mouse knockouts show social recognition deficits that can be remediated by oxytocin injections in the medial amygdala [163].”

What the sources say

• Not checked yetcites [163] Ferguson JN, Aldag JM, Insel TR, Young LJ. Oxytocin in the medial amygdala is essential for social recognition in the mouse. J Neurosci. 2001;21:8278–85. source

In the paper

“Low concentrations of oxytocin have been measured in the cerebellum in rats [161] but high densities of oxytocin receptors (OTR) are localized in the amygdala and are also found in parts of the hippocampus, hypothalamus, thalamus, mesencephalon and brainstem.”

What the sources say

• Not checked yetcites [161] Hashimoto H, Fukui K, Noto T, Nakajima T, Kato N. Distribution of vasopressin and oxytocin in rat brain. Endocrinol Jpn. 1985;32(1):89–97. source

In the paper

“Additionally, reductions in FMRP occurred in association with elevations in mGluR5 and decreases in GABAA β3 receptors indicating a linkage between these divergent molecular systems and pointing to potential therapeutic targets in autism.”

In the paper

“In conclusion, the above findings highlight the role of the GABAergic system, GAD enzymes, Reelin, glutamate receptors/transporters, mGluR5, and FMRP in autism.”

In the paper

“While significant reductions in GABAA and GABAB receptors have been observed in subjects with autism, decreased GAD 65 and 67 enzymes have also been found, suggesting impaired conversion of glutamate to GABA in these patients.”

In the paper

“From animal studies, the MAO projects to the anterior lobe, caudal vermis and the flocculus in cerebellar cortex and to the globose, emboliform and fastigial deep cerebellar nuclei, most of which show pathological abnormalities in autism [3].”

What the sources say

• Not checked yetcites [3] Bauman ML, Kemper TL. Histoanatomic observations of the brain in early infantile autism. Neurology. 1985;35:866–74. source

In the paper

“Improvements in repetitive behaviors in adults with autism following oxytocin infusion have been demonstrated [169] as well as positive effects on social behaviors and cognition [170].”

What the sources say

• Not checked yetcites [169] Hollander E, Novotny S, Hanratty M, Yaffe R, DeCaria CM, Aronowitz BR, et al. Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger’s disorders. Neuropsychopharm. 2003;28:193–8. source
• Not checked yetcites [170] Hollander E, Bartz J, Chaplin W, Phillips A, Sumner J, Soorya L, et al. Oxytocin increases retention of social cognition in autism. Biol Psychiatry. 2007;61:498–503. source

In the paper

“A follow up study [173] found increased α4 mRNA expression in cerebellum but subunit protein levels and binding decreased.”

What the sources say

• Not checked yetcites [173] Martin-Ruiz CM, Lee M, Perry RH, Baumann M, Court JA, Perry EK. Molecular analysis of nicotinic receptor expression in autism. Brain Res Mol Brain Res. 2004;123(1–2):81–90. source

In the paper

“Intranasal administration of oxytocin may reduce repetitive behaviors, and increase performance on tasks of social recognition [171].”

What the sources say

• Not checked yetcites [171] Bartz JA, Hollander E. Oxytocin and experimental therapeutics in autism spectrum disorders. Prog Brain Res. 2008;170:451–62. source

In the paper

“On the other hand, nicotinic cholinergic antagonists including some anti-depressants have helped ameliorate some autistic symptoms and are being explored as novel therapeutic agents [175].”

What the sources say

• Not checked yetcites [175] Lippiello PM. Nicotinic cholinergic antagonists: a novel approach for the treatment of autism. Med Hypotheses. 2006;66(5):985–90. source

In the paper

“In contrast, increased M2 cholinergic receptor expression in the MAO in normal developing infants compared to fetal binding has been reported [177], suggesting a possible role of muscarinic receptors as an early growth factor in infant development.”

What the sources say

• Not checked yetcites [177] Armstrong DD, Assman S, Kinney HC. Early developmental changes in the chemoarchitecture of the human inferior olive: a review. J Neuropathol Exp Neurol. 1999;58:1–11. source

In the paper

“Oxytocin may also interact with dopamine to modulate socio-affiliative behaviors and central oxytocin pathways may serve as therapeutic targets to improve mood and social behaviors [168].”

What the sources say

• Not checked yetcites [168] Baskerville TA, Douglas AJ. Dopamine and oxytocin interactions underlying behaviors: potential contributions to behavioral disorders. CNS Neurosci Ther. 2010;16(3):e92–e123. source

In the paper

“In this regard, nicotinic cholinergic receptor type α7 is located on the surface of GABA inhibitory neurons and selective stimulation of this receptor subtype would cause GABA release and play a role in restoring inhibitory tone [174].”

What the sources say

• Not checked yetcites [174] Deutsch SI, Urbano MR, Neumann SA, Burket JA, Katz E. Cholinergic abnormalities in autism: is there a rationale for selective nicotinic agonist interventions? Clin Neuropharmacol. 2010;33(3):114–20. source

In the paper

“Nicotinic agonists are thought to enhance attentional processes, cognition and memory and thus may be useful as a therapeutic tool.”

In the paper

“In development, the physiological balance of dopamine D1 and D2 receptor activation is critical for GABA neuron migration from the basal forebrain to the cerebral cortex and may contribute to developmental disorders such as autism [181].”

What the sources say

• Not checked yetcites [181] Crandall JE, McCarthy DM, Araki KY, Sims JR, Ren J-Q, Bhide PG. Dopamine receptor activation modulates GABA neuron migration from the basal forebrain to the cerebral cortex. J Neurosci. 2007;27(14):3813–22. source

In the paper

“An increased number of 5-HT axons and terminals were reported in a variety of brain regions via immunocytochemical labeling of 5-HT transporter in post-mortem autism subjects aged 2–29 years old bringing into question the wide use of SSRIs as therapeutic agents [187].”

What the sources say

• Not checked yetcites [187] Azmitia EC, Singh JS, Whitaker-Azmitia PM. Increased serotonin axons (immunoreactive to 5-HT transporter) in postmortem brains from young autism donors. Neuropharm. 2011;60:1347–54. source

In the paper

“In fact, Williams et al. [188] tested four SSRIs and concluded that there is no evidence of effect in autistic children and emerging evidence of harm, and limited evidence of effectiveness in autistic adults.”

What the sources say

• Not checked yetcites [188] Williams K, Wheeler DM, Silove N, Hazell P. Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2010;4(8):CD004677.

In the paper

“The dentato-thalamo-cortical neurons are thought to be glutamatergic and thus implicate glutamate as a modulator of mPFC dopaminergic activity [179].”

What the sources say

• Not checked yetcites [179] Rogers TD, Dickson PE, Heck DH, Goldowitz D, Mittleman G, Blaha CD. Connecting the dots of the cerebro-cerebellar role in cognitive function: neuronal pathways for cerebellar modulation of dopamine release in the prefrontal cortex. Synapse. 2011;65(11):1204–12. source

In the paper

“In normal post-mortem human cerebellum, there is a relatively low concentration of 5-HT transporters (SERT) compared to other brain regions except in the white matter and can be used as a reference region in binding studies looking at other brain regions with higher binding densities [184].”

What the sources say

• Not checked yetcites [184] Kish SJ, Furukawa Y, Chang L-J, Tong J, Ginovart N, Wilson A, et al. Regional distribution of serotonin transporter protein in post-mortem human brain: is the cerebellum a SERT-free brain region? Nucl Med Biol. 2005;32(2):123–8. source

In the paper

“It is noteworthy that some selective serotonin reuptake inhibitors (SSRIs) that target 5-HTT and 5-HTR may also target some dopamine receptor types.”

In the paper

“In a PET imaging study, serotonin transporter binding was reduced in the anterior and posterior cingulate cortex in high functioning autistic subjects associated with impaired social cognition and, in the thalamus associated with repetitive and /or obsessive behavior and interests [182].”

What the sources say

• Not checked yetcites [182] Nakamura K, Sekine Y, Ouchi Y, Tsujii M, Yoshikawa E, Futatsubashi M, et al. Brain serotonin and dopamine transporter bindings in adults with high-functioning autism. Arch Gen Psychiatry. 2010;67(1):58–68. source

In the paper

“In contrast, a high level of 5-HT5A mRNA expression was found in the cerebellum especially localized to Purkinje cells and in the granule cells and dentate nucleus in both hemispheres and the vermis and may contribute to emotional, cognitive and motor functions associated with autism [185].”

What the sources say

• Not checked yetcites [185] Marazziti D. A further support to the hypothesis of a link between serotonin, autism, and the cerebellum. Biol Psychiatry. 2002;52(2):143. source

In the paper

“It has been recently reported that cerebellar pathology in autism and other cognitive disorders could result from the functional loss of cerebellar-mPFC circuitry due to abnormal dopaminergic activity in the mPFC [179].”

What the sources say

• Not checked yetcites [179] Rogers TD, Dickson PE, Heck DH, Goldowitz D, Mittleman G, Blaha CD. Connecting the dots of the cerebro-cerebellar role in cognitive function: neuronal pathways for cerebellar modulation of dopamine release in the prefrontal cortex. Synapse. 2011;65(11):1204–12. source

In the paper

“For example, SSRIs and/or atypical antipsychotics that block both 5-HT2R and dopamine D1 and D2 receptors are especially attractive for possible clinical benefits [183].”

What the sources say

• Not checked yetcites [183] Buitelaar JK, Willemsen-Swinkels SH. Medication treatment in subjects with autistic spectrum disorders. Eur Child Adolesc Psychiatry. 2000;9(1):185–97.

In the paper

“Peripheral 5-HT effects in autism are well documented but central 5-HT differences are still emerging.”

In the paper

“Freitag et al. [198] found that gross and fine motor impairments are associated with the severity of autistic symptoms suggesting possible common pathophysiological mechanisms.”

What the sources say

• Not checked yetcites [198] Freitag CM, Kleser C, Schneider M, von Gontard A. Quantitative assessment of neuromotor function in adolescents with high functioning autism and Asperger Syndrome. J Autism Dev Disord. 2007;37(5):948–59. source

In the paper

“Recent studies have documented impaired vestibular control [197], and gross and fine motor abnormalities similar to those demonstrated by patients with established cerebellar disease [198].”

What the sources say

• Not checked yetcites [197] Molloy CA, Dietrich KN, Bhattacharya A. Postural stability in children with autism spectrum disorder. J Autism Dev Disord. 2003;33(6):643–52. source
• Not checked yetcites [198] Freitag CM, Kleser C, Schneider M, von Gontard A. Quantitative assessment of neuromotor function in adolescents with high functioning autism and Asperger Syndrome. J Autism Dev Disord. 2007;37(5):948–59. source

In the paper

“The majority of single-gene disorders associated with AD also are characterized by cerebellar pathology, suggesting that linking cerebellar structural abnormalities to core neurobehavioral features in AD may provide important insights into the etiology of these disorder(s) [190].”

What the sources say

• Not checked yetcites [190] Abrahams BS, Geschwind DH. Connecting genes to brain in the autism spectrum disorders. Arch Neurol. 2010;67(4):395–9. source

In the paper

“Cerebellar involvement in coordinated movements has been well described [310], and recent work indicates that the cerebellum plays an important role in non-motor functions as well [191] (Table 2).”

What the sources say

• Not checked yetcites [310] Manni E, Petrosini L. A century of cerebellar somatotopy: a debated representation. Nat Rev Neurosci. 2004;5(3):241–9. source
• Not checked yetcites [191] Leiner HC, Leiner AL, Dow RS. Does the cerebellum contribute to mental skills? Behav Neurosci. 1986;100(4):443–54. source

In the paper

“There is thus a considerable anatomical basis for distinguishing motor and cognitive cerebellar systems, but the extent to which each of these systems is functionally impaired in AD remains poorly understood.”

In the paper

“Sensorimotor pathways have been identified throughout the cerebellum, and preferential involvement of anterior lobules I–V and lobule VIII has been documented (Figure 5).”

In the paper

“AD is defined by three core symptom categories: social impairment, communication abnormalities, and restricted and repetitive behaviors.”

In the paper

“When performing gross motor movements during fMRI studies, individuals with AD show reduced ipsilateral anterior cerebellar activation [199] and more diffuse activation across lobules VI-VII [200].”

What the sources say

• Not checked yetcites [199] Mostofsky SH, Powell SK, Simmonds DJ, Goldberg MC, Caffo B, Pekar JJ. Decreased connectivity and cerebellar activity in autism during motor task performance. Brain. 2009;132(9):2413–25. source
• Not checked yetcites [200] Allen G, Courchesne E. Differential effects of developmental cerebellar abnormality on cognitive and motor functions in the cerebellum: an fMRI study of autism. Am J Psychiatry. 2003;160(2):262–73. source

In the paper

“Our recent findings that oculomotor deficits observed in individuals with AD also are present in unaffected family members suggest that dysfunctions within the oculomotor vermis may be familial and could serve as intermediate phenotypes for gene discovery [204].”

What the sources say

• Not checked yetcites [204] Mosconi MW, Kay M, D’Cruz AM, Guter S, Kapur K, Macmillan C, et al. Neurobehavioral abnormalities in first-degree relatives of individuals with autism. Arch Gen Psychiatry. 2010;67(8):830–40. source

In the paper

“Executive dysfunctions and attention deficits are well characterized in AD, but few studies have linked these impairments to cerebellar abnormalities.”

In the paper

“Verbal and spatial working memory deficits have been consistently documented in AD, but no known studies have reported an association with functional or structural abnormalities within the cerebellum.”

In the paper

“But, the primacy of the cerebellum to cognitive dysfunctions in AD remains unclear.”

In the paper

“Some memory functions are compromised in AD, although there is evidence that the extent to which subjects are impaired is strongly associated with the complexity of the task [205].”

What the sources say

• Not checked yetcites [205] Williams DL, Goldstein G, Minshew NJ. The profile of memory function in children with autism. Neuropsychology. 2006;20(1):21–9. source

In the paper

“FMRI studies of saccades and smooth pursuit document reduced activation within the posterior vermis, and increased involvement of association cortices and dentate nuclei in AD [203].”

What the sources say

• Not checked yetcites [203] Takarae Y, Minshew NJ, Luna B, Sweeney JA. Atypical involvement of frontostriatal systems during sensorimotor control in autism. Psychiatry Res. 2007;156(2):117–27. source

In the paper

“Pattern generators still play major life supporting roles (breathing, swallowing, chewing, walking and running etc.) in all vertebrate nervous systems today.”

In the paper

“In conclusion, cerebellar abnormalities are established in AD, and they may contribute to neurobehavioral deficits.”

In the paper

“The cerebellum’s crystalline network architecture is highly homogeneous throughout the entire structure, suggesting that one principle neuronal operation is performed in all parts of the cerebellum.”

In the paper

“Post-mortem anatomical studies of brains from autistic individuals thus far revealed loss of Purkinje cells in the posterior vermis and intermediate cerebellar cortex as the most consistent neuropathology, suggesting a key role of the cerebellum in autism [213].”

What the sources say

• Not checked yetcites [213] Courchesne E. Brainstem, cerebellar and limbic neuroanatomical abnormalities in autism. Curr Opin Neurobiol. 1997;7:269–78. source

In the paper

“Rhythmic stereotypic movements controlled by central pattern generator circuits are among the evolutionarily oldest and most important motor patterns.”

In the paper

“Yuste and colleagues recently suggested that the wiring diagram of the neocortical network is analogous to pattern generator circuits [218]”

What the sources say

• Not checked yetcites [218] Yuste R, MacLean JN, Smith J, Lansner A. The cortex as a central pattern generator. Nat Rev Neurosci. 2005;6:477–83. source

In the paper

“Movements, even simple ones, require precise spatiotemporal coordination of dozens of muscles and it is believed that the cerebellum is involved in coordinating the precise timing of muscle activities [215–217].”

What the sources say

• Not checked yetcites [215] Sasaki K, Gemba H. Cerebro-cerebellar interactions: for fast and stable timing of voluntary movement. In: Mano N, Hamada I, DeLong MR, editors. Role of the cerebellum and basal ganglia in voluntary movement. Amsterdam: Elsevier; 1993. p. 41–50.
• Not checked yetcites [216] Ivry RB, Keele SW, Diener HC. Dissociation of the lateral and medial cerebellum in movement timing and movement execution. Exp Brain Res. 1988;73:167–80. source
• Not checked yetcites [217] Braitenberg V. Is the cerebellar cortex a biological clock in the millisecond range? In: Fox CA, Snider RS, editors. Progress in Brain Research. Vol.25. The Cerebellum. Amsterdam: Elsevier; 1967. p. 334–46.

In the paper

“Reciprocal connections between neocortical motor and non-motor association areas and the cerebellum have also been carefully mapped out [211, 212].”

What the sources say

• Not checked yetcites [211] Kelly RM, Strick PL. Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate. J Neurosci. 2003;23:8432–44. source
• Not checked yetcites [212] Middleton FA, Strick PL. Cerebellar projections to the prefrontal cortex of the primate. J Neurosci. 2001;21:700–12. source

In the paper

“Molinari and colleagues also suggested that the cerebellum is crucially involved in analyzing sequential events, albeit in the behavioral domain, i.e. at a considerably slower time scale than the neuronal sequences discussed here [226].”

What the sources say

• Not checked yetcites [226] Molinari M, Chiricozzi FR, Clausi S, Tedesco AM, De Lisa M, Leggio MG. Cerebellum and detection of sequences, from perception to cognition. Cerebellum. 2008;7:611–5. source

In the paper

“The hypothesis presented here offers a possible answer to the question of how the cerebellum could contribute to motor and cognitive processes under the constraint that the same neuronal mechanism should apply to both functions.”

In the paper

“Important new clues, however, come from recent studies reporting cerebellar control of dopamine release in the prefrontal cortex [179, 180], a mechanism that might be triggered by spatiotemporal cortical activity patterns, as proposed here.”

What the sources say

• Not checked yetcites [179] Rogers TD, Dickson PE, Heck DH, Goldowitz D, Mittleman G, Blaha CD. Connecting the dots of the cerebro-cerebellar role in cognitive function: neuronal pathways for cerebellar modulation of dopamine release in the prefrontal cortex. Synapse. 2011;65(11):1204–12. source
• Not checked yetcites [180] Mittleman G, Goldowitz D, Heck DH, Blaha CD. Cerebellar modulation of frontal cortex dopamine efflux in mice: relevance to autism and schizophrenia. Synapse. 2008;62(7):544–50. source

In the paper

“It is interesting, that other researchers, based on clinical observations alone, suggested the terms “cognitive dysmetria” [227] or “dysmetria of thought” [31] to describe the effect of loss of cerebellar function on cognition, implying strong similarities between motor and cognitive cerebellar function.”

What the sources say

• Not checked yetcites [227] Andreasen NC, Paradiso S, O’Leary DS. “Cognitive dysmetria” as an integrative theory of schizophrenia: a dysfunction in cortical-subcortical-cerebellar circuitry? Schizophr. Bull. 1998;24:203–18.
• Not checked yetcites [31] Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain. 1998;121(4):561–79. source

In the paper

“Thus precisely timed spatiotemporal cortical activity patterns, transmitted through-and potentially transformed in-the pontine nuclei would be detected by the cerebellum and trigger specific and precisely timed responses in cerebellar output activity which would–via the thalamus-contribute to the coordination of neocortical network activity involved in cognitive or motor processes (Figure 6).”

In the paper

“in addition to broader diagnostic criteria and greater awareness, a real increase in incidence is also likely [230, 233].”

What the sources say

• Not checked yetcites [230] Persico AM, Bourgeron T. Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci. 2006;29:349–58. source
• Not checked yetcites [233] Landrigan PJ. What causes autism? Exploring the environmental contribution. Curr Opin Pediatr. 2010;22:219–25. source

In the paper

“The incidence of autism has dramatically risen during the last two decades from 2–5/10,000 to approximately 1–2/1,000 children [232];”

What the sources say

• Not checked yetcites [232] Fombonne E. Epidemiology of autistic disorder and other pervasive developmental disorders. J Clin Psychiatry. 2005;66 Suppl 10:3–8.

In the paper

“The anomalies most frequently reported include a smaller vermis volume, Purkinje cell numbers reduced by up to 50%, ectopic neurons in the white matter, and patchy cytoarchitectonic ectopias in the cerebellar cortex [32, 33, 118, 228, 229].”

What the sources say

• Not checked yetcites [32] Scott JA, Schumann CM, Goodlin-Jones BL, Amaral DG. A comprehensive volumetric analysis of the cerebellum in children and adolescents with autism spectrum disorder. Autism Res. 2009;2(5):246–57. source
• Not checked yetcites [33] Ritvo ER, Freeman BJ, Scheibel AB, Duong T, Robinson H, Guthrie D, et al. Lower Purkinje cell counts in the cerebella of four autistic subjects: initial findings of the UCLA–NSAC autopsy research project. Am J Psychiatry. 1986;143(7):862–6. source
• Not checked yetcites [118] Bauman ML, Kemper TL. Neuroanatomic observations of the brain in autism: a review and future directions. Int J Dev Neurosci. 2005;23:183–7. source
• Not checked yetcites [228] Courchesne E, Yeung-Courchesne R, Press GA, Hesselink JR, Jernigan TL. Hypoplasia of cerebellar vermal lobules VI and VII in autism. N Engl J Med. 1988;318:1349–54. source
• Not checked yetcites [229] Bauman ML. Microscopic neuroanatomic abnormalities in autism. Pediatrics. 1991;87:791–6. source

In the paper

“Secondly, genetics strongly contributes to the pathogenesis of AD, but many patients reveal no obviously pathogenic mutations or copy number variants, and initial heritability estimates as high as >90% [234] have been challenged by more recent twin studies [235].”

What the sources say

• Not checked yetcites [234] Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med. 1995;25:63–77. source
• Not checked yetcites [235] Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry. 2011;68(11):1095–102. source

In the paper

“However, the significant decrease in serum arylesterase, but not in diazoxonase PON1 activity recorded in our AD samples points toward excessive oxidative stress, previously documented in AD patients and boosted by OPs, as perhaps playing a more prominent role than acetylcholinesterase inhibition [236].”

What the sources say