gaba a and gaba b receptor abnormalities in autism

GABAGABAAA and GABA and GABABB

Receptor Receptor Abnormalities Abnormalities

in Autismin Autism

S. Hossein Fatemi, M.D., Ph.D.S. Hossein Fatemi, M.D., Ph.D.

Professor of Psychiatry, Professor of Psychiatry, Pharmacology and NeurosciencePharmacology and Neuroscience

University of Minnesota University of Minnesota Medical SchoolMedical School

Minneapolis, MN, USAMinneapolis, MN, USA

AutismAutismNeurodevelopmental disorderNeurodevelopmental disorder– Brain pathology involving parietal, frontal, cerebellar, Brain pathology involving parietal, frontal, cerebellar,

hippocampal, and amygdalar areashippocampal, and amygdalar areas– Early onset of diseaseEarly onset of disease

Genetic etiologiesGenetic etiologies– MZ concordance 36-95%MZ concordance 36-95%– Chromosomes 1, 5, 6, 8, 13, 15, 16, 18, 21, x, yChromosomes 1, 5, 6, 8, 13, 15, 16, 18, 21, x, y– HOX A, Reelin, WntHOX A, Reelin, Wnt

Environmental etiologiesEnvironmental etiologies– Rubella, borna, syphilis, CMV, mumpsRubella, borna, syphilis, CMV, mumps– ThalidomideThalidomide– Valproic acidValproic acid– MercuryMercury

Brain Pathology in AutismBrain Pathology in AutismSelective cortical atrophySelective cortical atrophy

Purkinje cell loss and atrophy Purkinje cell loss and atrophy (Piven; Fatemi)(Piven; Fatemi)

Smaller cingulate gyrusSmaller cingulate gyrus

Higher packing density and smaller neuron Higher packing density and smaller neuron size in hippocampus, amygdala and septal size in hippocampus, amygdala and septal nucleus nucleus (Bauman and Kemper)(Bauman and Kemper)

Macrocephaly Macrocephaly (Courchesne)(Courchesne)

Abnormal brain stemAbnormal brain stem

Microcolumnar pathology Microcolumnar pathology (Casanova et al.)(Casanova et al.)

Cell migration – ReelinCell migration – Reelin

GABA transmission – GADGABA transmission – GAD

Apoptosis – Bcl2 and P53Apoptosis – Bcl2 and P53

Cell injury – GFAPCell injury – GFAP

cAMP/cGMP modulation - PDEscAMP/cGMP modulation - PDEs

Pathological FindingsPathological Findings

MethodsMethods

SDS-PAGESDS-PAGE

Western BlottingWestern Blotting

qRT-PCRqRT-PCR

HPLCHPLC

Table 1. Demographic data for subjects with autism and controls

CaseCase DxDx SexSex AgeAgePMI PMI

(Hours)(Hours)EthnicityEthnicity Medication HistoryMedication History Cause of DeathCause of Death SeizureSeizure Brain AreasBrain Areas

B1078B1078 Autistic*Autistic* MM 2222 14.314.3 CaucasianCaucasianDilantin, Tegretol, Phenobarbital, Dilantin, Tegretol, Phenobarbital,

TheodureTheodureAsphyxiaAsphyxia YesYes BA40BA40

B1045B1045 Autistic*Autistic* MM 2828 16.316.3 CaucasianCaucasian Cefobid, Urecholine, DuracefCefobid, Urecholine, Duracef Cardiac arrestCardiac arrest YesYes Cer, BA40Cer, BA40

B5000B5000 Autistic*Autistic* MM 2727 8.38.3 CaucasianCaucasian SynthroidSynthroid DrowningDrowning NoNo CerCer

B1401B1401 Autistic*Autistic* FF 2121 20.620.6 CaucasianCaucasian TetracyclineTetracycline Pneumonia, sepsisPneumonia, sepsis YesYes Cer, BA9, BA40Cer, BA9, BA40

B1664B1664 Autistic*Autistic* MM 2020 1515 CaucasianCaucasian Vitamins B, CVitamins B, C Perforation of ulcer; asphyxiaPerforation of ulcer; asphyxia YesYes Cer, BA9, BA40Cer, BA9, BA40

B2825B2825 Autistic*Autistic* MM 1919 9.59.5 CaucasianCaucasian NoneNone SeizureSeizure YesYes Cer, BA9, BA40Cer, BA9, BA40

B3511B3511 Autistic*Autistic* MM 2929 1515 CaucasianCaucasian NoneNone Hit by trainHit by train YesYes Cer, BA9, BA40Cer, BA9, BA40

B3845B3845 Autistic*Autistic* MM 3030 28.428.4 CaucasianCaucasian Mellaril, Phenobarbital, DilantinMellaril, Phenobarbital, Dilantin Shock; acute pancreatitisShock; acute pancreatitis YesYes BA9, BA40BA9, BA40

B1484B1484 Autistic*Autistic* MM 1919 1515 CaucasianCaucasian NoneNone BurnsBurns NoNo BA9, BA40BA9, BA40

B3829B3829 ControlControl MM 2222 24.324.3 CaucasianCaucasian NoneNone MVAMVA NoNo CerCer

B4267B4267 ControlControl MM 2626 2020 African-AmericanAfrican-American NoneNone MVAMVA NoNo CerCer

B4268B4268 ControlControl MM 3030 2222 African-AmericanAfrican-American NoneNone CardiomyopathyCardiomyopathy NoNo Cer, BA40Cer, BA40

B4269B4269 ControlControl MM 2828 2424 CaucasianCaucasian Lidocaine 12.0 mg/L found in bloodLidocaine 12.0 mg/L found in bloodArteriosclerotic cardiovascular Arteriosclerotic cardiovascular

diseasediseaseNoNo Cer, BA9, BA40Cer, BA9, BA40

B4272B4272 ControlControl MM 1919 1717 CaucasianCaucasian NoneNone Accident; chest injuriesAccident; chest injuries NoNo CerCer

B4275B4275 ControlControl MM 2020 1616 CaucasianCaucasian NoneNone AccidentAccident NoNo Cer, BA9, BA40Cer, BA9, BA40

B4279B4279 ControlControl FF 2020 2121 CaucasianCaucasian NoneNone MVAMVA NoNo CerCer

B4362B4362 ControlControl MM 3030 2020 African-AmericanAfrican-American NoneNone MVAMVA NoNo Cer, BA9Cer, BA9

B4101B4101 ControlControl MM 2424 55 UnknownUnknown NoneNone Gun shot woundGun shot wound NoNo Cer, BA40Cer, BA40

B4271B4271 ControlControl MM 1919 2121 African-AmericanAfrican-American Ethyl alcohol, Advil, AmoxapineEthyl alcohol, Advil, Amoxapine EpiglottitisEpiglottitis NoNo BA40BA40

B4756B4756 ControlControl MM 5656 2323 UnknownUnknown NoneNone Cardiac arrestCardiac arrest NoNo CerCer

B4363B4363 ControlControl MM 2121 99 CaucasianCaucasian NoneNone MVAMVA NoNo Cer, BA40Cer, BA40

Dx, diagnosis; PMI, postmortem interval; M, male; F, female; Autistic*, all autistic subjects were also mentally retarded[2]; MVA, motor vehicle accident

Figure 1. Representative samples of GABRA1 (51 kDa), GABRA2 (51 kDa), GABRA3 (55 kDa), GABRA5 (52 kDa), GABRA6 (50 kDa), GABRG2 (45 kDa), GABRG3 (51 kDa), GABRB3 (56 kDa), GABBR1 (108 kDa), GABBR2 (105 kDa), and β-Actin (42 kDa) in BA9, BA40, and cerebellum of subjects with autism (A) and matched controls (C).

Table 2. Expression of GABRA1-GABRA3, GABRB3, GABBR1, and GABBR2 in cerebellum, BA40, and BA9 in subjects with autism vs. controls

CerebellumCerebellum ControlControl AutisticAutistic ChangeChange p*p* mRNAmRNA

GABRA1 / GABRA1 / ββ-Actin-Actin 1.350 1.350 ±± 0.470 0.470 0.504 0.504 ±± 0.356 0.356 ↓↓63%63% 0.0070.007 ncnc

GABRA2 / β-ActinGABRA2 / β-Actin 0.073 0.073 ±± 0.028 0.028 0.053 0.053 ±± 0.025 0.025 ↓↓27%27% 0.210.21 ncnc


GABRB3 / β-ActinGABRB3 / β-Actin 0.061 0.061 ±± 0.022 0.022 0.030 0.030 ±± 0.013 0.013 ↓↓51%51% 0.0080.008 ↓↓****

GABBR1 / β-ActinGABBR1 / β-Actin 0.051 ± 0.0180.051 ± 0.018 0.017 ± 0.0060.017 ± 0.006 ↓ ↓ 67%67% 0.0050.005 ↓↓****

GABBR2 / β-ActinGABBR2 / β-Actin 0.068 ± 0.0280.068 ± 0.028 0.037 ± 0.0120.037 ± 0.012 ↓ ↓ 46%46% 0.0260.026 ncnc

BA40BA40 ControlControl AutisticAutistic ChangeChange pp mRNAmRNA




GABRB3 / β-ActinGABRB3 / β-Actin 0.039 0.039 ±± 0.011 0.011 0.024 0.024 ±± 0.006 0.006 ↓↓38%38% 0.0060.006 ncnc






GABRA3 / β-ActinGABRA3 / β-Actin 0.127 0.127 ±± 0.006 0.006 0.193 0.193 ±± 0.083 0.083 ↑ ↑ 52%52% 0.2360.236 ncnc

GABRB3 / β-ActinGABRB3 / β-Actin 0.040 0.040 ±± 0.002 0.002 0.041 0.041 ±± 0.009 0.009 ↑↑2.5%2.5% 0.8530.853 ncnc



*, Two-tailed independent group t-tests; **, p<0.05; nc, no change

Table 3. Expression of GABRA5, GABRA6, GABRG2, and GABRG3 in cerebellum, BA40, and BA9 in subjects with autism vs. controls

CerebellumCerebellum ControlControl AutisticAutistic ChangeChange p*p* mRNAmRNA

GABRA5 / GABRA5 / ββ-Actin-Actin 0.387 0.387 ±± 0.194 0.194 0.436 0.436 ±± 0.152 0.152 ↑↑3%3% 0. 520. 52 ncnc

GABRA6 / β-ActinGABRA6 / β-Actin 0.417 0.417 ±± 0.134 0.134 0.442 0.442 ±± 0.195 0.195 ↑↑6%6% 0.750.75 ncnc

GABRG2 / β-ActinGABRG2 / β-Actin 0.153 0.153 ±± 0.084 0.084 0.122 0.122 ±± 0.057 0.057 ↓↓%% 0.410.41 ncnc

GABRG3 / β-ActinGABRG3 / β-Actin 0.313 0.313 ±± 0.089 0.089 0.331 0.331 ±± 0.070 0.070 ↑↑6%6% 0.650.65 ncnc



GABRA6 / β-ActinGABRA6 / β-Actin 0.198 0.198 ±± 0.071 0.071 0.286 0.286 ±± 0.092 0.092 ↑↑44%44% 0.130.13 ncnc

GABRG2 / β-ActinGABRG2 / β-Actin 0.255 0.255 ±± 0.137 0.137 0.198 0.198 ±± 0.050 0.050 ↓↓22%22% 0.460.46 ncnc

GABRG3 / β-ActinGABRG3 / β-Actin 0.229 0.229 ±± 0.075 0.075 0.246 0.246 ±± 0.061 0.061 ↑↑7%7% 0.720.72 ncnc






*, Two-tailed independent group t-tests; **, p<0.05; nc, no change

Figure 2. Neurochemical analysis of brain regions of control and autistic subjects in BA9 (A), BA40 (B), and cerebellum (C). Shown are mean values ± SEM of the mean for dopamine (DA), serotonin (5-HT), glutamate (Glu), glutamine (Gln), taurine (tau), and GABA. Statistical significance of difference analyzed by one way analysis of variance followed by Holm Sidak post hoc test. **p<0.05

Protein LevelsProtein Levels GABAGABAAA 1 protein by 63% in cerebellum1 protein by 63% in cerebellum

GABAGABAAA 3 protein by 51% in cerebellum3 protein by 51% in cerebellum

GABAGABABB R1 protein by 67% in cerebellum R1 protein by 67% in cerebellum

GABAGABABB R2 protein by 46% in cerebellum R2 protein by 46% in cerebellum

GABAGABAAA 1 protein by 52% in BA401 protein by 52% in BA40




GABAGABABB R1 protein by 71% in BA40 R1 protein by 71% in BA40


GABAGABABB R1 protein by 70% in BA9 R1 protein by 70% in BA9

HPLC StudiesHPLC Studies cerebellar serotonin (cerebellar serotonin (pp<0.05) in autism<0.05) in autism

No difference in levels of GABA, No difference in levels of GABA, glutamate, dopamine, glycine, or taurine glutamate, dopamine, glycine, or taurine between two groupbetween two group

Supported by central serotonergic Supported by central serotonergic hypofunction in autism hypofunction in autism (Croonenbergh (Croonenbergh et alet al., ., 2007)2007)

mRNA LevelsmRNA Levels

mRNA for GABAmRNA for GABAAA 3 levels by 29% in 3 levels by 29% in

cerebella of autistics vs. controlscerebella of autistics vs. controls

mRNA for GABAmRNA for GABABB R1 levels by 15% in R1 levels by 15% in

cerebella of autistics vs. controlscerebella of autistics vs. controls

GABAGABAAA 33Implicated by multiple association studies in autism Implicated by multiple association studies in autism (Buxbaum JD (Buxbaum JD et alet al., 2002; Cook EH ., 2002; Cook EH et alet al., 1998; McCauley JL ., 1998; McCauley JL et alet al., 2004; Shao Y ., 2004; Shao Y et alet al., 2003)., 2003) expression in autism, Angelman syndrome and expression in autism, Angelman syndrome and Rett’s disease Rett’s disease (Samaco RC (Samaco RC et alet al., 2005)., 2005)

Pentameric chloride channelsPentameric chloride channelsCrucial site of action for intravenous anesthetics, Crucial site of action for intravenous anesthetics, ethanol, and developmental processes (i.e., ethanol, and developmental processes (i.e., ventromedial nucleus of hypothalamus)ventromedial nucleus of hypothalamus)Localized to 15q11-q13, a site for Localized to 15q11-q13, a site for 3, 3, 5, and 5, and 3 3 subunits of GABAsubunits of GABAAA receptor receptorOur results are the first to show significant decreases Our results are the first to show significant decreases in in 3 proteins in cerebellum and BA40 of autistics, as 3 proteins in cerebellum and BA40 of autistics, as well as well as 3 mRNA and protein decreases in cerebellum 3 mRNA and protein decreases in cerebellum of autisticsof autistics

GABAGABABB R1 R1Signal transduction/G protein activation Signal transduction/G protein activation (Jones KA (Jones KA et alet al., ., 2000)2000)

Downregulation in kainic acid-induced seizures in rats Downregulation in kainic acid-induced seizures in rats signify neurodegeneration signify neurodegeneration (Furtingers (Furtingers et alet al., 2003)., 2003)

Impairment of attentional processing Impairment of attentional processing (Prosser HM (Prosser HM et alet al., ., 2001)2001)

Ca-dependent receptor activation; tubulin-dependent Ca-dependent receptor activation; tubulin-dependent receptor traffickingreceptor trafficking

Insulin resistance, hyperlocomotion, and atypical Insulin resistance, hyperlocomotion, and atypical absence seizureabsence seizure

Our results are the first to demonstrate R1 deficiency Our results are the first to demonstrate R1 deficiency in 3 important brain areas in autismin 3 important brain areas in autism

GABAGABABB R2 R2Gene locus at 9q22.1Gene locus at 9q22.1

G-protein coupled receptor 51G-protein coupled receptor 51

Associated with nicotine dependenceAssociated with nicotine dependence

Increased with absence seizure in rat Increased with absence seizure in rat somatosensory cortex and thalamus somatosensory cortex and thalamus (Principalle (Principalle et al., 2003)et al., 2003)

GABAGABAAA 11Gene locus 5q34-q35Gene locus 5q34-q35

Associated with juvenile myoclonic epilepsyAssociated with juvenile myoclonic epilepsy

Associated with depression in probands Associated with depression in probands (Murray (Murray et alet al., 1994)., 1994)

5HT1A receptor in brains of subjects with JME 5HT1A receptor in brains of subjects with JME (Meschaks (Meschaks et alet al., 2005).., 2005). Serotonin is reduced in Serotonin is reduced in cerebellum of autistics cerebellum of autistics (Fatemi (Fatemi et alet al., 2008)., 2008)

No previous publication indicating its reduction No previous publication indicating its reduction in autismin autism

GABAGABAAA 22Gene locus at 4p12Gene locus at 4p12Modulates anxiety and stress responseModulates anxiety and stress responseMay be involved in plasticity of ventrobasal May be involved in plasticity of ventrobasal complex and posterior nucleus of thalamus in complex and posterior nucleus of thalamus in chronic inflammatory pain chronic inflammatory pain (Ferreria-Gomes (Ferreria-Gomes et alet al., ., 2006)2006)

Expression in medial amygdala Expression in medial amygdala (Byrnes (Byrnes et alet al., ., 2007)2007)

Involved in hippocampal dentate granule cell Involved in hippocampal dentate granule cell during development during development (Brooks-Kayal (Brooks-Kayal et alet al., 2001)., 2001)

Associated with alcohol dependence Associated with alcohol dependence (Soyka (Soyka et et alal., 2008)., 2008)

GABAGABAAA 33Gene locus at Xq28Gene locus at Xq28

Localized to substantia nigra parvalbumin-Localized to substantia nigra parvalbumin-positive nonpigmented cells positive nonpigmented cells (Waldvogel et al., (Waldvogel et al., 2008)2008)

Involved in unipolar major depression Involved in unipolar major depression (Henket et (Henket et al., 2004)al., 2004)

GABAGABAAA 55Gene locus at 15q11.2-q12Gene locus at 15q11.2-q12

Component of a pentameric receptor mediating Component of a pentameric receptor mediating inhibitory neurotransmissioninhibitory neurotransmission

Involved in the susceptibility to schizophrenia Involved in the susceptibility to schizophrenia (Papadimitriou et al., 2001a)(Papadimitriou et al., 2001a) and bipolar affective and bipolar affective disorder disorder (Papadimitriou et al., 2001b; Otani et al., (Papadimitriou et al., 2001b; Otani et al.,

2005)2005)

Implicated in autism Implicated in autism (Menold et al., 2001; Ashley-(Menold et al., 2001; Ashley-

Koch et al., 2005; Tochigi et al., 2007),Koch et al., 2005; Tochigi et al., 2007), Angelman Angelman syndrome syndrome (Nurmi et al., 2001),(Nurmi et al., 2001), and childhood and childhood absence epilepsy (CAE) absence epilepsy (CAE) (Lu et al., 2004)(Lu et al., 2004)

GABAGABAAA 66Gene locus at 5q34Gene locus at 5q34

Component of a pentameric receptor mediating Component of a pentameric receptor mediating inhibitory neurotransmission, expressed in the inhibitory neurotransmission, expressed in the cerebellar granule cells and the related cells of cerebellar granule cells and the related cells of cochlear nucleuscochlear nucleus

Implicated in schizophrenia (Implicated in schizophrenia (Petryshen et al., Petryshen et al.,

2005),2005), alcoholism alcoholism (Chang et al., 2002; Dick et al., (Chang et al., 2002; Dick et al.,

2003; Sen et al., 2004),2003; Sen et al., 2004), and heroin abuse and heroin abuse (Loh et (Loh et al., 2007)al., 2007)

GABAGABAAA 22Gene locus at 5q31.1-q33.1Gene locus at 5q31.1-q33.1This subunit carries the benzodiazepine binding siteThis subunit carries the benzodiazepine binding siteComponent of a pentameric receptor mediating inhibitory Component of a pentameric receptor mediating inhibitory neurotransmission, complexing with DRD5 and promoting neurotransmission, complexing with DRD5 and promoting mutually inhibitory functional interactions between these mutually inhibitory functional interactions between these receptor systems receptor systems Implicated in schizophrenia (Petryshen et al., 2005) and mood Implicated in schizophrenia (Petryshen et al., 2005) and mood disorders (Yamada, 2003)disorders (Yamada, 2003)Involved in the physiological dependence on alcohol (Sander Involved in the physiological dependence on alcohol (Sander et al., 1999; Chang et al., 2002; Dick et al., 2003), heroin et al., 1999; Chang et al., 2002; Dick et al., 2003), heroin abuse (Loh et al., 2007), and methamphetamine abuse abuse (Loh et al., 2007), and methamphetamine abuse (Nishiyama et al., 2005)(Nishiyama et al., 2005)Cause of childhood absence epilepsy type 2 (ECA2) (Olsen et Cause of childhood absence epilepsy type 2 (ECA2) (Olsen et al., 1999; Wallace et al., 2001) generalized epilepsy with al., 1999; Wallace et al., 2001) generalized epilepsy with febrile seizures plus type 3 (GEFS+3) (Baulac et al., 2001) febrile seizures plus type 3 (GEFS+3) (Baulac et al., 2001) severe myoclonic epilepsy in infancy (SMEI)(Jansen et al., severe myoclonic epilepsy in infancy (SMEI)(Jansen et al., 2006)2006)

GABAGABAAA 33Gene locus at 15q12Gene locus at 15q12

This subunit also carries the benzodiazepine This subunit also carries the benzodiazepine binding site binding site

Component of a pentameric receptor Component of a pentameric receptor mediating inhibitory neurotransmissionmediating inhibitory neurotransmission

Associated with alcohol dependence Associated with alcohol dependence (Dick et (Dick et al., 2004)al., 2004)

Associated with risk for autism Associated with risk for autism (Ma et al., 2005; (Ma et al., 2005; Ashley-Koch et al., 2006)Ashley-Koch et al., 2006)

Glutamic Acid Decarboxylase 65kDaGlutamic Acid Decarboxylase 65kDa

Localized to axon terminals Localized to axon terminals

Membrane bound and in vesiclesMembrane bound and in vesicles

Involved in vesicular release of GABAInvolved in vesicular release of GABA

Involved in synthesis of GABA by phasically Involved in synthesis of GABA by phasically firing neuronsfiring neurons

Can exist as either amphiphillic GAD65 Can exist as either amphiphillic GAD65 homodimer or GAD65/67 heterodimerhomodimer or GAD65/67 heterodimer

Glutamic Acid Decarboxylase 67kDaGlutamic Acid Decarboxylase 67kDa Concentrated in interneuronsConcentrated in interneurons

CytosolicCytosolic

Involved in non-vesicular synthesis of GABAInvolved in non-vesicular synthesis of GABA

Involved in continuous synthesis of GABA in Involved in continuous synthesis of GABA in tonically firing neuronstonically firing neurons

Used for synthesis of GABA for general Used for synthesis of GABA for general metabolic activitymetabolic activity

Can exist as either hydrophillic GAD67 Can exist as either hydrophillic GAD67 homodimer or amphiphillic GAD65/67 homodimer or amphiphillic GAD65/67 homodimerhomodimer

Glutamate & aspartateGlutamate & aspartate in plasma of autistic children in plasma of autistic children (Moreno et al., 1992; Moreno-Fuenmayer et al., 1996)(Moreno et al., 1992; Moreno-Fuenmayer et al., 1996)

CSF glutamateCSF glutamate in 4 patients with Rett’s syndrome in 4 patients with Rett’s syndrome (Hamberger et al., 1992)(Hamberger et al., 1992)

Glutamate & GABAGlutamate & GABA in platelets of drug-naïve in platelets of drug-naïve autistic patients (Rolf et al., 1993)autistic patients (Rolf et al., 1993)

Glutamate to N-acetylaspartate ratioGlutamate to N-acetylaspartate ratio in gray in gray matter in Rett’s syndrome (Pan et al., 1999) matter in Rett’s syndrome (Pan et al., 1999)

mRNA of excitatory amino acid transporter 1 and mRNA of excitatory amino acid transporter 1 and AMPA1 receptorAMPA1 receptor with with density of AMPA1 receptor in density of AMPA1 receptor in autistic cerebellum (Purcell et al., 2001)autistic cerebellum (Purcell et al., 2001)

GAD 65/67 in Parietal Cortex

GAD 65/67 in Cerebellum

ConclusionsConclusionsGABAGABAAA 1 and 1 and 3, GABA3, GABABB R1 and R2 proteins R1 and R2 proteins

decreased in cerebellum of autistics (decreased in cerebellum of autistics (pp<0.05)<0.05)

GABAGABAAA 1, 1, 2, 2, 3, and 3, and 3 and GABA3 and GABABB R1 proteins R1 proteins

decreased in BA40 of autistics (decreased in BA40 of autistics (pp<0.05)<0.05)

GABAGABAAA 1, 1, 5, 5, 6, 6, 2, and GABA2, and GABABB R1 proteins R1 proteins

decreased in BA9 of autistics (decreased in BA9 of autistics (pp<0.05)<0.05)

GABAGABAAA 3 and GABA3 and GABABB R1 mRNAs decreased in R1 mRNAs decreased in

cerebellum of autistics (cerebellum of autistics (pp<0.05)<0.05)

Serotonin levels reduced in cerebellum of autistics Serotonin levels reduced in cerebellum of autistics without any change in levels of glutamate or GABAwithout any change in levels of glutamate or GABA

Results support Results support ↑ ↑ rates of seizure disorder and mental rates of seizure disorder and mental retardation in autistic subjectsretardation in autistic subjects

AcknowledgementsAcknowledgements

Human tissue was obtained from the NICHD Brain and Tissue Bank for Developmental Disorders; the Harvard Brain Tissue Resource Center, which is supported in part by PHS grant number R24 MH068855; the Brain Endowment Bank, which is funded in part by the National Parkinson Foundation, Inc., Miami, Florida; and the Autism Tissue Program and is gratefully acknowledged. Grant support by National Institute of Child Health and Human Development (#5R01HD052074-01A2) to SHF is also gratefully acknowledged.

CollaboratorsCollaboratorsUniversity of Minnesota, Minneapolis, MN USA- TJ Reutiman, TD Folsom, PD Thuras

Charité Campus Mitte, University Medicine, Berlin, Germany- C Winter, R Sohr, J Klein

University of Rochester, Rochester, NY USA- DA Pearce, M Zanche

gaba a and gaba b receptor abnormalities in autism

Documents

cerebellum of subjects

autistic subjects

expression of gabra1

expression of gabra5

female autistic

matched controls

smaller neuron size

septal nucleus bauman