Suppressed GABAergic inhibition as a common factor in suspected etiologies of autism (PDF)
John P. Hussman, Ph.D., Journal of Autism & Developmental Disorders, April 2001

While the cause of autism remains unknown, this 2001 piece was the first published hypothesis that disruptions in the GABA system may operate as a central factor mediating the disorder - acting as a common thread between various suspected causes of autism. The key idea is that there may a variety of etiologies such as genetic predisposition, perinatal infection, etc. having the capacity to disrupt the GABA system, but once disrupted, autistic pathology results because the ability to gate and filter sensory information and neural cross-talk is suppressed. This hypothesis is widely consistent with various functional and neuroanatomical characteristics of autism. Subsequent research has also been increasingly supportive of this view.

The following papers are part of an ongoing research partnership with Dr. Margaret Pericak-Vance and Dr. Jeffery Vance, now of the Institute of Human Genomics at the University of Miami, to identify genetic factors involved in autism:

Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism.
Ma DQ, Whitehead PL, Menold MM, Martin ER, Ashley-Koch AE, Mei H, Ritchie MD, Delong GR, Abramson RK, Wright HH, Cuccaro ML, Hussman JP, Gilbert JR, Pericak-Vance MA.  American Journal of Human Genetics. 2005 Sep;77(3):377-88

An analysis paradigm for investigating multi-locus effects in complex disease: examination of three GABA receptor subunit genes on 15q11-q13 as risk factors for autistic disorder.
Ashley-Koch AE, Mei H, Jaworski J, Ma DQ, Ritchie MD, Menold MM, Delong GR, Abramson RK, Wright HH, Hussman JP, Cuccaro ML, Gilbert JR, Martin ER, Pericak-Vance MA. Ann Hum Genet. 2006 May;70(Pt 3):281-92.

Investigation of autism and GABA receptor subunit genes in multiple ethnic groups.
Collins AL, Ma DQ, Whitehead PL, Martin ER, Wright HH, Abramson RK, Hussman JP, Haines JL, Cuccaro ML, Gilbert JR, Pericak-Vance MA. Neurogenetics. 2006 Jul;7(3):167-74. Epub 2006 Jun 13

Other research supported by the Hussman Foundation:

Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications.
Yip J, Soghomonian JJ, Blatt GJ. Acta Neuropathol (Berl). 2007 Jan 18; Epub.

Further research in support of the hypothesis linking autism and suppressed GABAergic inhibitory tone:

15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders.
Hogart A, Nagarajan RP, Patzel KA, Yasui DH, Lasalle JM. Hum Mol Genet. 2007 Mar 5; Epub.

An inversion inv(4)(p12-p15.3) in autistic siblings implicates the 4p GABA receptor gene cluster.
Vincent JB, Horike SI, Choufani S, Paterson AD, Roberts W, Szatmari P, Weksberg R, Fernandex B, Scherer SW. Journal of Med. Genet., 2006 May;43(5):429-34. Epub 2006 Mar 23.

A linkage disequilibrium map of the 1-Mb 15q12 GABA(A) receptor subunit cluster and association to autism.
McCauley JL, Olson LM, Delahanty R, Amin T, Nurmi EL, Organ EL, Jacobs MM, Folstein SE, Haines JL, Sutcliffe JS. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. Am J Med Genet B Neuropsychiatr Genet. 2004 Nov 15;131(1):51-9.

Disruption in the inhibitory architecture of the cell minicolumn: implications for autism
Casanova MF, Buxhoeveden D, Gomez J., Neuroscientist. 2003 Dec;9(6):496-507.

Exploratory subsetting of autism families based on savant skills improves evidence of genetic linkage to 15q11-q13
Nurmi EL, Dowd M, Tadevosyan-Leyfer O, Haines JL, Folstein SE, Sutcliffe JS. J Am Acad Child Adolesc Psychiatry. 2003 Jul;42(7):856-63.

Association between a GABRB3 polymorphism and autism.
Buxbaum JD, Silverman JM, Smith CJ, Greenberg DA, Kilifarski M, Reichert J, Cook EH Jr, Fang Y, Song CY, Vitale R., Mol Psychiatry. 2002;7(3):311-6.

Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study.
Blatt GJ, Fitzgerald CM, Guptill JT, Booker AB, Kemper TL, Bauman ML., J Autism Dev Disord. 2001 Dec;31(6):537-43.

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