Consensus Paper: Pathological Role of the Cerebellum in Autism

In the paper

“Compellingly, however, many genes converge on common biological pathways and brain circuits. These include synaptic formation, signaling and homeostasis in brain regions that process rapid and coherent integration of information from multiple, higher-level association areas, including frontal and temporal cortices, caudate, amygdala and cerebellum [55–58].”

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
• Partly supported

  In “Candidates and Compatriots,” the paper describes interactions among autism susceptibility genes and a shared signaling pathway. “Synthesis of an Integrated Model” discusses synaptic formation or maintenance and altered connectivity involving frontal and temporal regions and the amygdala. Our copy does not substantiate the claim’s added synaptic homeostasis or its inclusion of the caudate and cerebellum in those circuits. Page numbers were not available in the indexed passages. (LLM, conf=0.87)

  cites [56] Bill BR, Geschwind DH. Genetic advances in autism: heterogeneity and convergence on shared pathways. Curr Opin Genet Dev. 2009;19(3):271–8. sourceExperimental — accuracy not yet measured
• Partly supported

  In “Connecting Genes to Brain and Behavior” (page unavailable), the paper says ASD susceptibility genes must converge on disrupted function in brain regions involved in language and social cognition, and discusses synaptic dysfunction and neural transmission. But it explicitly says whether the genes converge on common molecular pathways is unresolved; the cited passages do not identify synaptic homeostasis or the specific brain regions listed in the claim. (LLM, conf=0.87)

  cites [57] Geschwind DH. Autism: many genes, common pathways? Cell. 2008;135(3):391–5. sourceExperimental — accuracy not yet measured
• Not checked yetcites [58] Geschwind DH, Levitt P. Autism spectrum disorders: developmental disconnection syndromes. Curr Opin Neurobiol. 2007;17(1):103–11. source

In the paper

“As recently reviewed [32], some, but not all, tracing and voxel-based morphometry studies of young children, adolescents and adults with AD find evidence for increased cerebellar volume.”

What the sources say

• Partly supported

  In Discussion > Comparison with previous findings (page not provided), the paper reports that an earlier study found enlarged total cerebellar volume in autistic males aged 12–52. Its own Results > Cerebellum and major subregions (page not provided) find no difference in total cerebellar volume, supporting the mixed-findings point. The passages do not substantiate the claim specifically about voxel-based morphometry studies or young children. (LLM, conf=0.83)

  cites [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. sourceExperimental — accuracy not yet measured

In the paper

“In cerebellum, concordant reductions have been observed in mRNA and protein levels for GABAB R1 receptor in subjects with autism [130].”

What the sources say

• Supported

  The Results report a 67% reduction in cerebellar GABBR1 protein in subjects with autism compared with controls and significant downregulation of cerebellar GABBR1 mRNA. The Discussion explicitly describes these findings as concordant. Page numbers are not provided in our copy. (LLM, conf=0.94)

  cites [130] Fatemi SH, Reutiman TJ, Folsom TD, Rooney PJ, Patel DH, Thuras PD. mRNA and protein levels for GABAAalpha4, alpha5, beta1, and GABABR1 receptors are altered in brains from subjects with autism. J Autism Dev Disord. 2010;40:743–50. source

In the paper

“No relationship was observed between Purkinje cell number and performance on a sustained attention task [286].”

What the sources say

• Not checked yetcites [286] Martin LA, Goldowitz D, Mittleman G. Sustained attention in the mouse: a study of the relationship with the cerebellum. Behav Neurosci. 2006;120(2):477–81. source

In the paper

“Lurcher mice with a total absence of Purkinje cells showed marked attenuations in cerebellar stimulation-evoked dopamine transmission in the medial PFC (Figure 9, bottom)”

In the paper

“(3) investigatory nose poking in a hole-board exploration task [287].”

What the sources say

• Not checked yetcites [287] Martin LA, Goldowitz D, Mittleman G. Repetitive behavior and increased activity in mice with Purkinje cell loss: a model for understanding the role of cerebellar pathology in autism. Eur J Neurosci. 2010;31:544–55. source

In the paper

“First, the developmental loss of cerebellar Purkinje cells affected performance on some, but not all executive functions.”

In the paper

“(2) activity in an open field,”

In the paper

“we found a negative relationship between Purkinje cell number and (1) repetitive lever pressing in a progressive ratio task,”

In the paper

“but, surprisingly, facilitated working memory performance on a delayed matching-to-position task [285].”

What the sources say

• Not checked yetcites [285] Martin LA, Escher T, Goldowitz D, Mittleman G. A relationship between cerebellar Purkinje cells and spatial working memory demonstrated in a lurcher/chimera mouse model system. Genes Brain Behav. 2004;3:158–66. source

In the paper

“mice with reduced Purkinje cell numbers displayed impaired performance on the later stages of a non-spatial serial reversal learning task, a measure of behavioral flexibility [284],”

What the sources say

• Not checked yetcites [284] Dickson PE, Rogers TD, Del Mar N, Martin LA, Heck D, Blaha CD, et al. Behavioral flexibility in a mouse model of developmental cerebellar Purkinje cell loss. Neurobiol Learn Mem. 2010;94:220–8. source

In the paper

“One of the most consistently abnormal brain regions has been the cerebellum and areas related to it.”

In the paper

“almost all of the postmortem brains of autistic individuals studied to date, regardless of age, sex, and cognitive ability, have shown a significant decrease in the number of Purkinje cells (PC), primarily in the posterolateral neocerebellar cortex and adjacent archicerebellar cortex of the cerebellar hemispheres [4–7].”

What the sources say

• Not checked yetcites [4] Arin DM, Bauman ML, Kemper TL. The distribution of Purkinje cell loss in the cerebellum in autism. Neurology. 1991;41(Suppl):307.
• Not checked yetcites [5] Bailey A, Luthert P, Dean A, Harding B, Janota I, Montgomery M, et al. A clinicopathological study of autism. Brain. 1998;121:889–905. source
• 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
• Not checked yetcites [7] Bauman ML, Kemper TL, editors. The neurobiology of autism. Baltimore: Johns Hopkins University Press; 2005.

In the paper

“Many of these functions may be disordered in autism and it is possible that the cerebellar abnormalities noted in the brains of autistic individuals contribute to these clinical features in autism.”

In the paper

“Cerebellar maintenance of posture, balance, motor dexterity and coordination of movement is impaired in some individuals with AD [20, 21].”

What the sources say

• Not checked yetcites [20] Fournier KA, Hass CJ, Naik SK, Lodha N, Cauraugh JH. Motor coordination in autism spectrum disorders: a synthesis and meta-analysis. J Autism Dev Disord. 2010;40(10):1227–40. source
• Not checked yetcites [21] Minshew NJ, Sung K, Jones B, Furman JM. Underdevelopment of the postural control system in autism. Neurology. 2004;63(11):2056–61. source

In the paper

“In the brains of autistic individuals with loss of PCs there is no neuronal loss in the synaptically related inferior olive. This tight relationship is established shortly before birth. Once this bond is made, any loss of PCs thereafter results in an obligatory retrograde cell loss of inferior olivary neurons [6, 10, 11].”

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
• Not checked yetcites [10] Holmes G, Stewart TG. On the connection of the inferior olives with the cerebellum in man. Brain. 1908;31:125–37. source
• Not checked yetcites [11] Greenfield JG, Greenfield JG. The spino-cerebellar degenerations. Springfield: CC Thomas; 1954.

In the paper

“Prospective studies of infants at high genetic risk for AD implicate motor impairment as among the earliest signs of the autism phenotype [22].”

What the sources say

• Not checked yetcites [22] Ozonoff S, Young GS, Goldring S, Greiss-Hess L, Herrera AM, Steele J, et al. Gross motor development, movement abnormalities, and early identification of autism. J Autism Dev Disord. 2008;38:644–56. source

In the paper

“In summary, histoanatomic abnormalities of the cerebellum are one of the most consistent neuroanatomic findings in the brains of autistic individuals.”

In the paper

“Deficits in eye blink conditioning in AD [49] and after cerebellar lesions [50] provide evidence for an altered olivocerebellar “clock-signal” for sensory timing that occurs below the level of perceptual awareness [51] as illustrated in Figure 1.”

What the sources say

• Not checked yetcites [49] Oristaglio J, Ghaffari M, Hyman West S, Welsh JP, Malone R. A sensory timing abnormality in autism revealed by classical eyeblink conditioning. Soc Neurosci Abstr. 2012; (in press).
• Not checked yetcites [50] Gerwig M, Esser AC, Guberina H, Frings M, Kolb FP, Forsting M, et al. Trace eyeblink conditioning in patients with cerebellar degeneration: comparison of short and long trace intervals. Exp Brain Res. 2008;187:85–96. source
• Not checked yetcites [51] Welsh JP, Ahn ES, Placantonakis DG. Is autism due to brain desynchronization? Int J Dev Neurosci. 2005;23:253–63. source

In the paper

“Recent fMRI and lesion data indicate that the olivocerebellar system is especially involved in the timing of intervals defined by successive sensory events occurring over the range of 100–600ms.”

In the paper

“Analysis of syndromic AD patients now provides clear support for a cerebellar role.”

In the paper

“One striking feature is the presence of on-going neuroinflammation in postmortem brain tissue from individuals with AD, a finding that is consistent over a broad age range (5–44 years of age) [73].”

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

“Moreover, increases in many cytokines and chemokines are observed in the brain and cerebrospinal fluid (CSF) of individuals with AD, in particular; interleukin (IL)-6, transforming growth factor beta 1 (TGFβ1), C-C motif ligand 2 (CCL2) and CCL17 in the cerebellum [73–76].”

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
• Not checked yetcites [74] Chez MG, Dowling T, Patel PB, Khanna P, Kominsky M. Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr Neurol. 2007;36(6):361–5. source
• Not checked yetcites [75] Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li XM, et al. Elevated immune response in the brain of autistic patients. J Neuroimmunol. 2009;207:111–6. source
• Not checked yetcites [76] Wei H, Zou H, Sheikh AM, Malik M, Dobkin C, Brown WT, et al. IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation. J Neuroinflammation. 2011;8:52. source

In the paper

“Children diagnosed with AD are not routinely evaluated for structural brain malformations, but 10% of AD patients at one center were reported to have cerebellar abnormalities consistent with a Dandy-Walker malformation diagnosis [67].”

What the sources say

• Not checked yetcites [67] Miles JH, Hillman RE. Value of a clinical morphology examination in autism. Am J Med Genet. 2000;91(4):245–53. source

In the paper

“However, it is significant that the presence of antibodies against cerebellar proteins is strongly associated with worsening aberrant behavior [79].”

What the sources say

• Not checked yetcites [79] Goines P, Haapanen L, Boyce R, Duncanson P, Braunschweig D, Delwiche L, et al. Autoantibodies to cerebellum in children with autism associate with behavior. Brain Behav Immun. 2011;25:514–23. source

In the paper

“Three promising AD-implicated genes (EN2, GABRB3 and MET), identified from studies of non-syndromic AD, each with independent, replicated genetic evidence, have known and specific roles in cerebellar development.”

What the sources say

• Not checked yetcites SFARI Gene

In the paper

“In the cerebellum, the levels of lipid hydroperoxide [103], a product of fatty acid oxidation; of malonyldialdehyde [104], an end-product of lipid peroxidation; of 8-hydroxy-2’-deoxyguanosine (8-OH-dG) [105, 106], a marker of oxidative DNA damage; of protein carbonyl [107], a marker of protein oxidation; and of 3-nitrotyrosine [108], a marker of protein nitration, were significantly increased in”

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 [106] Sajdel-Sulkowska EM, Xu M, Koibuchi N. Increase in cerebellar neurotrophin-3 and oxidative stress markers in autism. Cerebellum. 2009;8:366–72. source

In the paper

“Taken together, the evidence thus far reported indicates a key role of immune dysfunction in the pathogenesis of AD.”

In the paper

“Reelin is an important protein expressed in GABAergic and glutamatergic cells [133, 134].”

What the sources say

• Not checked yetcites [133] Pesold C, Pisu MG, Impagnatiello F, Uzunov DP, Caruncho HJ. Reelin is preferentially expressed in neurons synthesizing gamma-aminobutyric acid in cortex and hippocampus of adult rats. Proc Natl Acad Sci. 1998;95:3221–6. source
• Not checked yetcites [134] Sinagra M, Gonzalez Campo C, Verrier D, Moustié O, Manzoni OJ, Chavis P. Glutamatergic cerebellar granule neurons synthesize and secrete reelin in vitro. Neuron Glia Biol. 2008;4:189–96. source

In the paper

“Fatemi et al. [126] was the first group to measure reductions in Reelin in post-mortem autistic cerebellum.”

What the sources say

• Not checked yetcites [126] Fatemi SH, Stary JM, Halt AR, Realmuto GR. Dysregulation of Reelin and Bcl-2 proteins in autistic cerebellum. J Autism Dev Disord. 2001;31:529–35. source

In the paper

“It has been shown that GAD 65 and 67 proteins are reduced in the cerebella of subjects with autism [122, 125].”

What the sources say

• Not checked yetcites [122] Fatemi SH, Halt AR, Stary JM, Kanodia R, Schulz SC, Realmuto GR. Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol Psychiatry. 2002;52(8):805–10. source
• Not checked yetcites [125] Yip J, Soghomonian JJ, Blatt GJ. Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications. Acta Neuropathol. 2007;113(5):559–68. source

In the paper

“The glutamatergic and gamma-aminobutyric acid (GABA) systems are important foci of pathology in the cerebella of patients with autism.”

In the paper

“In conclusion, elevated oxidative stress in the cerebellum and frontal and temporal lobes of individuals with autism suggests that oxidative stress may be a contributing factor in the pathophysiology and clinical development of autism.”

In the paper

“Additionally, other studies have reported reduced GABAA [129, 130] and GABAB [124, 130] receptor density and system activity in the brains of autistic patients.”

What the sources say

• Not checked yetcites [129] Blatt GJ, Fitzgerald CM, Guptill JT, Booker AB, Kemper TL, Bauman ML. Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study. J Autism Dev Disord. 2001;31(6):537–43. source
• Not checked yetcites [130] Fatemi SH, Reutiman TJ, Folsom TD, Rooney PJ, Patel DH, Thuras PD. mRNA and protein levels for GABAAalpha4, alpha5, beta1, and GABABR1 receptors are altered in brains from subjects with autism. J Autism Dev Disord. 2010;40:743–50. source
• Not checked yetcites [124] Fatemi SH, Folsom TD, Reutiman TJ, Thuras PD. Expression of GABA(B) receptors is altered in brains of subjects with autism. Cerebellum. 2009;8:64–9. source

In the paper

“Moreover, imbalance between GABA/glutamate can cause seizure disorders in autism.”

In the paper

“Genetic studies have found positive associations between autism and a number of polymorphisms in glutamate receptors and transporters including the mitochondrial aspartate-glutamate carrier (SLC25A12) [151] and glutamate receptor, ionotropic kainate 2 (GRIK2) [152, 153].”

What the sources say

• Not checked yetcites [151] Silverman JM, Buxbaum JD, Ramoz N, Schmeidler J, Reichenberg A, Hollander E, et al. Autism-related routines and rituals associated with a mitochondrial aspartate/glutamate carrier SLC25A12 polymorphism. Am J Med Genet B Neuropsychiatr Genet. 2008;147:408–10. source
• Not checked yetcites [152] Strutz-Seebohm N, Korniychuk G, Schwarz R, Baltaev R, Ureche ON, Mack AF, et al. Functional significance of the kainate receptor GluR6(M836I) mutation that is linked to autism. Cell Physiol Biochem. 2006;18:287–94. source
• Not checked yetcites [153] Kim SA, Kim JH, Park M, Cho IH, Yoo HJ. Family-based association study between GRIK2 polymorphisms and autism spectrum disorders in Korean trios. Neurosci Res. 2007;58:332–5. source

In the paper

“Through these receptors, Reelin is able to activate Disabled1 (Dab-1), an intracellular adapter protein that facilitates signaling between Reelin-secreting cells and pyramidal cells [147].”

What the sources say

• Not checked yetcites [147] Strasser V, Fasching D, Hauser C, Mayer H, Bock HH, Hiesberger T, et al. Receptor clustering is involved in Reelin signaling. Mol Cell Biol. 2004;24:1378–86. source

In the paper

“However, to date there have been only a limited number of studies showing altered expression of mRNA for glutamate receptors and transporters in brain [154, 155].”

What the sources say

• Not checked yetcites [154] Purcell AE, Jeon OH, Zimmerman AW, Blue ME, Pevsner J. Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology. 2001;57:1618–28. source
• Not checked yetcites [155] Lepagnol-Bestel AM, Maussion G, Boda B, Cardona A, Iwayama Y, Delezoide AL, et al. SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects. Mol Psychiatry. 2008;13:385–97. source

In the paper

“Deficiencies in social behaviors and OTRs in autism may in part be due to dysregulation of GABA via reduced reelin in autism [167].”

What the sources say

• Not checked yetcites [167] Liu W, Pappas GD, Carter CS. Oxytocin receptors in brain cortical regions are reduced in the haploinsufficient (+/−) reeler mice. Neurol Res. 2005;27(4):339–45. source

In the paper

“Research in animal models suggest a central role of oxytocin in mediating complex social behaviors with emphasis on action on OTRs in the amygdala to reduce fear and modulate aggression [162].”

What the sources say

• Not checked yetcites [162] Kirsch P, Meyer-Lindenberg A. Oxytocin and autism. In: Blatt Gene J, editor. The neurochemical basis of autism: from molecules to minicolumns. New York: Springer; 2010. p. 163–73. source

In the paper

“Moreover, Reelin signaling is also impaired in autism.”

In the paper

“The absence of FMRP in mouse knockout models has demonstrated upregulation of mGluR5 and PSD-95 translation [159, 160].”

What the sources say

• Not checked yetcites [159] Muddashetty RS, Kelić S, Gross C, Xu M, Bassell GJ. Dysregulated metabotropic glutamate receptor-dependent translation of AMPA receptor and postsynaptic density-95 mRNAs at synapses in a mouse model of fragile x syndrome. J Neurosci. 2007;27:5338–48. source
• Not checked yetcites [160] Bear MF, Huber KM, Warren ST. The mGluR theory of fragile X mental retardation. Trends Neurosci. 2004;27:370–7. source

In the paper

“Experiments in prairie voles have revealed central roles for oxytocin in modulating a variety of emotional and social behaviors [164–166].”

What the sources say

• Not checked yetcites [164] McCarthy MM, McDonald CH, Brooks PJ, Goldman D. An anxiolytic action of oxytocin is enhanced by estrogen in the mouse. Physiol Behav. 1996;60:1209–15. source
• Not checked yetcites [165] Insel TR, Young LJ. The neurobiology of attachment. Nat Rev Neurosci. 2001;2:129–36. source
• Not checked yetcites [166] Winslow JT, Insel TR. Neuroendocrine basis of social recognition. Curr Opin Neurobiol. 2004;14:248–53. source

In the paper

“Recent postmortem work has shown reductions in FMRP in cerebella and frontal cortices of subjects with autism who do not carry a mutation for FXS [123, 128].”

What the sources say

• Not checked yetcites [123] Fatemi SH, Folsom TD. Dysregulation of fragile X mental retardation protein and metabotropic glutamate receptor 5 in superior frontal cortex of individuals with autism: a postmortem brain study. Mol Autism. 2011;2:6. source
• Not checked yetcites [128] Fatemi SH, Folsom TD, Kneeland RE, Liesch SB. Metabotropic glutamate receptor 5 upregulation in children with autism is associated with underexpression of both Fragile X mental retardation protein and GABA A receptor beta 3 in adults with Autism. Anat Rec. 2011;294(10):1635–45. source

In the paper

“The cerebellum receives a dopaminergic pathway from the ventral tegmental area/substantia nigra pars compacta [178].”

What the sources say

• Not checked yetcites [178] Kolasiewicz W, Kuter K, Nowak P, Pastuszka A, Ossowska K. Lesion of the cerebellar noradrenergic innervation enhances the harmaline-induced tremor in rats. Cerebellum. 2011;10(2):267–80. source

In the paper

“Interestingly, no changes in muscarinic M1 or M2 type receptors were found in the cerebellum [172]”

What the sources say

• Not checked yetcites [172] Lee M, Martin-Ruiz C, Graham A, Court J, Jaros E, Perry R, et al. Nicotinic receptor abnormalities in the cerebellar cortex in autism. Brain. 2002;125(Pt 7):1483–95. source

In the paper

“In contrast, a three-fold increase in nicotinic cholinergic receptor type α7 measured by receptor binding using α-bungarotoxin was found in the granule cell layer.”

What the sources say

• Not checked yetcites [172] Lee M, Martin-Ruiz C, Graham A, Court J, Jaros E, Perry R, et al. Nicotinic receptor abnormalities in the cerebellar cortex in autism. Brain. 2002;125(Pt 7):1483–95. source

In the paper

“Key findings of 40–50% reduced nicotinic cholinergic receptor type α3, α4, and β2 measured by the high affinity agonist epibatidine in post-mortem autism cases relative to matched controls was reported in the granule cell, Purkinje cell and molecular layers in the cerebellum [172].”

What the sources say

• Not checked yetcites [172] Lee M, Martin-Ruiz C, Graham A, Court J, Jaros E, Perry R, et al. Nicotinic receptor abnormalities in the cerebellar cortex in autism. Brain. 2002;125(Pt 7):1483–95. source

In the paper

“A significant reduction in SERT but not the dopamine transporter (DAT) was found in medial frontal cortex in autistic children determined by SPECT imaging [186].”

What the sources say

• Not checked yetcites [186] Makkonen I, Riikonen R, Kokki H, Airaksinen MM, Kuikka JT. Serotonin and dopamine transporter binding in children with autism determined by SPECT. Dev Med Child Neurol. 2008;50(8):593–7. source

In the paper

“There is evidence that activation of the serotonergic system in the inferior olive and cerebellum can contribute to the enhancement of harmaline-induced tremor in animals, once thought to only be attributable to olivocerebellar release of glutamate acting on NMDAR and AMPAR [178].”

What the sources say

• Not checked yetcites [178] Kolasiewicz W, Kuter K, Nowak P, Pastuszka A, Ossowska K. Lesion of the cerebellar noradrenergic innervation enhances the harmaline-induced tremor in rats. Cerebellum. 2011;10(2):267–80. source

In the paper

“In a PET study, elevated dopamine transporter levels were reported in the orbitalfrontal cortex in high functioning autism subjects [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

“MRI studies have reported hypoplasia restricted to lobules I–V and vermal lobules VI-VII [189].”

What the sources say

• Not checked yetcites [189] Stanfield AC, McIntosh AM, Spencer MD, Philip R, Gaur S, Lawrie SM. Towards a neuroanatomy of autism: a systematic review and meta-analysis of structural magnetic resonance imaging studies. Eur Psychiatry. 2008;23(4):289–99. source

In the paper

“Stimulation of the dentate nuclei evokes dopamine release in the medial prefrontal cortex (mPFC).”

In the paper

“Post-mortem studies have documented reduced Purkinje cell size and number in autistic disorder (AD) [5].”

What the sources say

• Not checked yetcites [5] Bailey A, Luthert P, Dean A, Harding B, Janota I, Montgomery M, et al. A clinicopathological study of autism. Brain. 1998;121:889–905. source

In the paper

“Accumulating evidence indicates that the majority of affected individuals demonstrate motor impairments as well.”

In the paper

“In contrast, cognitive operations primarily involve posterior lobules VI-VII/Crus I–II [192].”

What the sources say

• Not checked yetcites [192] Stoodley CJ, Schmahmann JD. Functional topography in the human cerebellum: a meta-analysis of neuroimaging studies. NeuroImage. 2009;44(2):489–501. source

In the paper

“In their original descriptions of AD, Leo Kanner [195] and Hans Asperger [196] noted awkward motility and clumsiness.”

What the sources say

• Not checked yetcites [195] Kanner L. Autistic disturbances of affective contact. The Nervous Child. 1943;2:217–50.
• Not checked yetcites [196] Asperger H. ‘Autistic psychopathy’ in childhood. In: Frith U, editor. Autism and Asperger syndrome. New York: Cambridge University Press; 1991. p. 37–92. source

In the paper

“Ascending cerebellar fibers innervate motor cortices via caudal fastigial nuclei, interpositus nuclei, and dorsal segments of dentate nuclei [193].”

What the sources say

• Not checked yetcites [193] Middleton FA, Strick PL. Cerebellar output channels. Int Rev Neurobiol. 1997;41:61–82. source

In the paper

“Posterior “cognitive” lobules synapse within ventrolateral units of the dentate nuclei [194].”

What the sources say

• Not checked yetcites [194] Bloedel JR, Bantli H. A spinal action of the dentate nucleus mediated by descending systems originating in the brain stem. Brain Res. 1978;153(3):602–7. source

In the paper

“Muller et al. [201] and Mostofsky et al. [199] found concomitant increases in activation within association cortices and posterior cerebellum suggesting compensatory involvement of neocerebellar and neocortical pathways.”

What the sources say

• Not checked yetcites [201] Muller RA, Pierce K, Ambrose JB, Allen G, Courchesne E. Atypical patterns of cerebral motor activation in autism: a functional magnetic resonance study. Biol Psychiatry. 2001;49(8):665–76. source
• 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

In the paper

“Reversed asymmetry of lobule VIIIA also was related to deficits on clinical measures of language function in AD.”

What the sources say

• Not checked yetcites [208] Hodge SM, Makris N, Kennedy DN, Caviness Jr VS, Howard J, McGrath L, et al. Cerebellum, language, and cognition in autism and specific language impairment. J Autism Dev Disord. 2010;40(3):300–16. source

In the paper

“Individuals with AD typically demonstrate language impairments.”

In the paper

“Also, Hodge et al. [208] reported that the typical right greater than left volume of lateral posterior cerebellar lobules VII-VIII/Crus I–II was reversed in language impaired individuals with AD.”

What the sources say

• Not checked yetcites [208] Hodge SM, Makris N, Kennedy DN, Caviness Jr VS, Howard J, McGrath L, et al. Cerebellum, language, and cognition in autism and specific language impairment. J Autism Dev Disord. 2010;40(3):300–16. source

In the paper

“Reversed structural and functional asymmetry within fronto-temporal language cortices may contribute to these impairments [207].”

What the sources say

• Not checked yetcites [207] Herbert MR, Harris GJ, Adrien KT, Ziegler DA, Makris N, Kennedy DN, et al. Abnormal asymmetry in language association cortex in autism. Ann Neurol. 2002;52(5):588–96. source

In the paper

“Consistent with findings from manual motor testing, these results suggest that alterations of cerebellar motor systems may contribute to compensatory recruitment of non-motor cortical and cerebellar systems.”

In the paper

“Conjugate eye movements are modulated by vermal lobules VI-VII and caudal fastigial nuclei.”

In the paper

“Findings of reduced smooth pursuit velocity [202], hypometric saccades, and increased trial-to-trial variability of saccade amplitude [24] implicate vermal dysfunction in AD.”

What the sources say

• Not checked yetcites [202] Takarae Y, Minshew NJ, Luna B, Krisky CM, Sweeney JA. Pursuit eye movement deficits in autism. Brain. 2004;127(Pt 12):2584–94. 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

In the paper

“Schmahmann and Sherman [31] documented similar cognitive impairments in patients with chronic cerebellar disease.”

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

“Townsend et al. [206] found slower shift of attention was associated with reduced volumes of vermal lobules VI-VII.”

What the sources say

• Not checked yetcites [206] Townsend J, Courchesne E, Covington J, Westerfield M, Harris NS, Lyden P, et al. Spatial attention deficits in patients with acquired or developmental cerebellar abnormality. J Neurosci. 1999;19(13):5632–43. source

In the paper

“Allen and Courchesne [200] documented reduced activation in the posterior vermis during an attention shifting task.”

What the sources say

• 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

“Recent data suggests that dysfunction within posterior lobules VI-VIII may contribute to impaired higher cognitive functions as well.”

In the paper

“Studies of motor control consistently implicate anterior lobules I–VI and posterior vermal lobules VI-VII in AD, and imaging studies have identified compensatory involvement of cortico-striatal and posterior cerebellar systems.”

In the paper

“Studies of motor control consistently implicate anterior lobules I–VI and posterior vermal lobules VI-VII in AD, and imaging studies have identified compensatory involvement of cortico-striatal and posterior cerebellar systems.”

In the paper

“In addition to a crucial cerebellar role in motor coordination, strong correlations between cerebellar neuropathology and cognitive abnormalities in disorders like autism, schizophrenia and other cerebellar cognitive syndromes have been well established [18, 209, 210].”

What the sources say

• Not checked yetcites [18] Schmahmann J. The cerebellum and cognition. International review of neurobiology, vol. 41. San Diego: Academic; 1997.
• Not checked yetcites [209] Stoodley CJ. The cerebellum and cognition: evidence from functional imaging studies. Cerebellum. 2012; (in press). source
• Not checked yetcites [210] Gordon N. The cerebellum and cognition. Eur J Paediatr Neurol. 2007;11:232–4. source

In the paper

“This adds the interesting constraint that cerebellar contributions to motor coordination and cognitive functions are based on the same or highly similar neuronal computations.”

In the paper

“This concept receives additional support from electrophysiological findings showing that the neocortex generates precisely timed spatiotemporal spike activity patterns during various motor and non-motor cognitive tasks [219–221].”

What the sources say

• Not checked yetcites [219] Ayzenshtat I, Meirovithz E, Edelman H, Werner-Reiss U, Bienenstock E, Abeles M, et al. Precise spatiotemporal patterns among visual cortical areas and their relation to visual stimulus processing. J Neurosci. 2010;30:11232–45. source
• Not checked yetcites [220] Ben-Shaul Y, Drori R, Asher I, Stark E, Nadasdy Z, Abeles M. Neuronal activity in motor cortical areas reflects the sequential context of movement. J Neurophysiol. 2004;91:1748–1762. 7. source
• Not checked yetcites [221] Prut Y, Vaadia E, Bergman H, Haalman I, Slovin H, Abeles M. Spatiotemporal structure of cortical activity: properties and behavioral relevance. J Neurophysiol. 1998;79:2857–74. source

In the paper

“The same cerebellar input-output transformation involved in the temporal coordination of motor related cortical activity would apply to cognitive cortical activity.”

In the paper

“The specific arrangement of parallel fibers and Purkinje cells in the cerebellar cortex forms a network that specifically detects precisely timed sequences of input activity and generates precisely timed output activity in response [223–225].”

What the sources say

• Not checked yetcites [223] Heck DH. Rat cerebellar cortex in vitro responds specifically to moving stimuli. Neurosci Lett. 1993;157:95–8. source
• Not checked yetcites [224] Heck DH. Sequential input to guinea pig cerebellar cortex in vitro strongly affects Purkinje cells via parallel fibers. Naturwissenschaften. 1995;82:201–3. source
• Not checked yetcites [225] Braitenberg V, Heck DH, Sultan F. The detection and generation of sequences as a key to cerebellar function. Experiments and theory. Behav Brain Sci. 1997;20:229–45. source

In the paper

“The nature of cerebellar input-output transformation has been suggested to involve the detection of precisely timed activity patterns [222].”

What the sources say

• Not checked yetcites [222] Braitenberg V, Atwood RP. Morphological observations on the cerebellar cortex. J Comp Neurol. 1958;109:1–33. source

In the paper

“Here it is proposed that the precise spatiotemporal spike activity patterns generated in motor and non-motor areas of the conscious neocortex represent the cognitive equivalents of muscle activity patterns responsible for generating movements.”

In the paper

“It is furthermore suggested that the cerebellar contribution to cognition and motor control lies in the detection and coordination of spatiotemporal cortical activity patterns representing cognitive processes or motor commands.”

In the paper

“Those patterns are comparable to muscle activity patterns in duration, temporal precision and complexity.”

In the paper

“The cerebellum was the first brain region shown in the late 80’s to host neuroanatomical abnormalities in many autistic individuals [33, 228, 229].”

What the sources say

• 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 [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

“The RELN gene encodes for reelin, a stop signal protein critical to neuronal migration in the cerebral and cerebellar cortices.”

In the paper

“Among several mechanisms, this function also relies on a proteolytic activity exerted by reelin on extracellular matrix proteins, which is inhibited by organophosphate (OP) pesticides [134].”

What the sources say

• Not checked yetcites [134] Sinagra M, Gonzalez Campo C, Verrier D, Moustié O, Manzoni OJ, Chavis P. Glutamatergic cerebellar granule neurons synthesize and secrete reelin in vitro. Neuron Glia Biol. 2008;4:189–96. source

In the paper

“Other brain regions also display abnormalities generally resulting from reduced programmed cell death and/or increased cell proliferation, altered cell migration, and abnormal cell differentiation with reduced neuronal size and abnormal wiring [118, 230].”

What the sources say

• 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 [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

In the paper

“These neurodevelopmental processes physiologically occurs during the first and second trimester of pregnancy [231].”

What the sources say

• Not checked yetcites [231] Rice D, Barone Jr S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000;108 Suppl 3:511–33. source

In the paper

“Therefore, although the onset of deficits in social interaction and communication, stereotypies and insistence on sameness generally occurs after a postnatal time window of apparently normal behavior, autistic disorder is viewed by most experts as a neurodevelopmental disorder with prenatal origin or at least with essential prenatal components.”

In the paper

“Finally, the validity of gene-environment interaction models is also supported by known prenatal teratological agents, such as rubella or cytomegalovirus infection, and drugs like thalidomide, misoprostol, and valproic acid, which cause autism only in a subset of presumably vulnerable individuals [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

“Hence individuals carrying genetic variants expressing reduced amounts of Reelin and PON1 enzyme, if exposed prenatally to OPs during critical periods in neurodevelopment, could be more likely to suffer from altered neuronal migration resulting in AD [230].”

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

In the paper

“Several lines of evidence, including rare mutations affecting calcium (Ca2+) conductance in humans, indicate that excessive Ca2+ signalling plays a pivotal role in the pathophysiology of autism [243].”

What the sources say

• Not checked yetcites [243] Krey J, Dolmetsch R. Molecular mechanisms of autism: a possible role for Ca2+ signaling. Curr Opin Neurobiol. 2007;17:112–9. source

In the paper

“Very recent and exciting data indeed show: (a) an association between prenatal exposure to OPs, PON1 genotypes, and poorer neurobehavioral development in humans [241]”

What the sources say

• Not checked yetcites [241] Eskenazi B, Huen K, Marks A, Harley KG, Bradman A, Barr DB, et al. PON1 and neurodevelopment in children from the CHAMACOS study exposed to organophosphate pesticides in utero. Environ Health Perspect. 2010;118:1775–81. source

In the paper

“the MET receptor tyrosine kinase, encoded by the MET protooncogene, exerts an important role in the nervous, gastrointestinal and immune systems, by modulating cell proliferation and migration, as well as neurite outgrowth and synaptogenesis.”

In the paper

“Therefore, individuals carrying the MET C allele at rs1858830 and prenatally exposed to PAHs may be particularly at risk of undergoing abnormal neurodevelopment leading to cognitive or autistic symptoms.”

In the paper

“MET mRNA and protein levels are decreased by as much as 50% in AD brains compared to matched controls [251].”

What the sources say

• Not checked yetcites [251] Campbell DB, D’Oronzio R, Garbett K, Ebert PJ, Mirnics K, Levitt P, et al. Disruption of cerebral cortex MET signaling in autism spectrum disorder. Ann Neurol. 2007;62:243–50. source

In the paper

“This field is especially promising for cerebellar neuropathology, in light of the prolonged developmental time window exposing cerebellar circuits to damage by environmental agents in genetically susceptible individuals not only prenatally, but also postnatally [231].”

What the sources say

• Not checked yetcites [231] Rice D, Barone Jr S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000;108 Suppl 3:511–33. source

In the paper

“Its developmental role in the cerebellum is especially well established both in mammals and in zebrafish, albeit with evolutionarily determined species specificities [250].”

What the sources say

• Not checked yetcites [250] Elsen GE, Choi LY, Prince VE, Ho RK. The autism susceptibility gene met regulates zebrafish cerebellar development and facial motor neuron migration. Dev Biol. 2009;335:78–92. source

In the paper

“ATP2B2 gene variants possibly yielding reduced gene expression in post-mortem brains have recently been found associated with autism in males [247].”

What the sources say

• Not checked yetcites [247] Carayol J, Sacco R, Tores F, Rousseau F, Lewin P, Hager J, et al. Converging evidence for an association of ATP2B2 allelic variants with autism in males. Biol Psychiatry. 2011;70(9):880–7. source

In the paper

“Indeed, to the extent that the therapeutic armamentarium is aimed in a specific way at autism, the specificity derives from neurotransmitter systems broadly, or in some cases receptor subtypes, such as metabotropic glutamate receptors like mGluR5 [255], that are known or believed likely to influence the development or expression of core or related autism symptoms.”

What the sources say

• Not checked yetcites [255] Carlson GC. Glutamate receptor dysfunction and drug targets across models of autism spectrum disorders. Pharmacol Biochem Behav. 2012;100(4):850–4. source

In the paper

“Also SLC25A12 gene variants have been found associated with either liability or protection from autism [249].”

What the sources say

• Not checked yetcites [249] Palmieri L, Persico AM. Mitochondrial dysfunction in autism spectrum disorders: cause or effect? Biochim Biophys Acta. 2010;1797:1130–7. source

In the paper

“PCBs are important endocrine disruptors which, among several other effects, perturb intracellular Ca2+ signalling by promoting Ca2+ entry and by enhancing Ca2+ release from the endoplasmic reticulum through ryanodine receptors [248].”

What the sources say

• Not checked yetcites [248] Pessah IN, Cherednichenko G, Lein PJ. Minding the calcium store: ryanodine receptor activation as a convergent mechanism of PCB toxicity. Pharmacol Ther. 2010;125:260–85. source

In the paper

“Strategies to target specific brain structures or neuroanatomical pathways have not yet been utilized in the service of autism therapeutics.”

In the paper

“Casting a broader net, cerebellar involvement cannot be excluded from a number of behaviors often associated with autism that are very common pharmacological treatment targets -- including hyperactivity, aggression, irritability, and mood symptoms [258].”

What the sources say

• Not checked yetcites [258] Schmahmann JD, Weilburg JB, Sherman JC. The neuropsychiatry of the cerebellum—insights from the clinic. Cerebellum. 2007;6:254–67. source

In the paper

“Here again, symptomatic improvement may be mediated in important ways by drug effects on the cerebellum.”

In the paper

“The cerebellar hemispheres have been linked to several higher-order cerebral functions including language, working memory, planning and behavioral sequencing [e.g., 192, 256].”

What the sources say

• Not checked yetcites [192] Stoodley CJ, Schmahmann JD. Functional topography in the human cerebellum: a meta-analysis of neuroimaging studies. NeuroImage. 2009;44(2):489–501. source
• Not checked yetcites [256] Steinlin M. Cerebellar disorders in childhood: cognitive problems. Cerebellum. 2008;7:607–10. source

In the paper

“GABAergic dysfunction in the cerebellum in autism has been demonstrated repeatedly [70, 124, 261].”

What the sources say

• Not checked yetcites [70] Fatemi SH, Reutiman TJ, Folsom TD, Thuras PD. GABA(A) receptor downregulation in brains of subjects with autism. J Autism Dev Disord. 2009;39(2):223–30. source
• Not checked yetcites [124] Fatemi SH, Folsom TD, Reutiman TJ, Thuras PD. Expression of GABA(B) receptors is altered in brains of subjects with autism. Cerebellum. 2009;8:64–9. source
• Not checked yetcites [261] Blatt GJ. GABAergic cerebellar system in autism: a neuropathological and developmental perspective. Int Rev Neurobiol. 2005;71:167–78. source

In the paper

“Moreover, T-type calcium channels are a powerful mechanism by which the IO regulates cerebellar output [269].”

What the sources say

• Not checked yetcites [269] Park YG, Park HY, Lee CJ, Choi S, Jo S, Choi H, et al. Ca(V)3.1 is a tremor rhythm pacemaker in the inferior olive. Proc Nat Acad Sci (USA). 2010;107:10731–6. source

In the paper

“IO neurons are a compelling drug target, not simply because of their ability to control cerebellar output, but also due to their unique complement of ionic channels and neurotransmitter receptors.”