Neurochemical Mechanisms in Disease P41 potx

Neurochemistry of Autism 385 et al., 1988). Moreover, a murine model of prenatal viral infection that results in autistic-like behavior in offspring (Shi et al., 2003), has demonstrated that infection on embryonic day 16 (E16) and E18 which correspond to mid- and late second trimester, respectively, results in reduced levels of serotonin in cerebella of exposed offspring (Fatemi et al., 2008; Winter et al., 2008). Hyperserotonemia has been a consistent finding in subjects with autism, which may be due to activity of serotonin-associated platelet proteins (Hranilovi ´ c et al., 2008, 2009). Interestingly, 99% of blood serotonin is contained in platelets (Anderson et al., 1987) and studies have shown that there is an approximate 50% increase in blood-levels of serotonin in subjects with autism vs. controls (McBride et al., 1998). Hypotheses for increased serotonin include increased synthesis of serotonin by tryptophan hydroxylase (TPH1), increased uptake of serotonin into platelets via serotonin transporters (5-HTT), diminished release of serotonin f rom platelets via serotonin 2A receptor, and decreased breakdown of serotonin by monoamine oxidase (MAOA) (Hranilovic et al., 2008). A study by Hranilovic et al. (2008) identified polymorphisms of tryptophan hydroxylase and MAOA with increased serum serotonin levels. Similarly, haplotype analysis has shown a significant association between polymorphisms of TPH1 and increased serotonin in whole blood (Cross et al., 2008). The serotonin transporter gene 5-HTT (also known as SLC6A4) has been the f ocus of much research as a potential candidate gene for autism (Cook and Leventhal, 1996; Ozaki et al., 2003). 5-HTT modulates serotonergic neurotransmission by active reuptake of serotonin from the synaptic cleft (Amara and Pacholczyk, 1991). Of the over 20 polymorphisms of 5-HTT, there are two that are of interest due to their functional effects: (1) 5-HTTLPR which has a deletion/insertion at the 5  -flanking regulatory region that results in a long variant (L) and a short variant (S) (Heils et al., 1996). The short variant reduces the efficiency of the 5-HT gene pro- moter and results in lower gene expression and serotonin uptake ability (Heils et al., 1996); and (2) STin2 which has a variable number of tandem repeats in the second intron and results in three common alleles: STin2.9, STin2.10, and STin2.12 indicat- ing 9, 10, and 12 repeats, respectively (Lesch et al., 1996). A recent meta-analysis of family-based and population-based association studies for 5-HTT found no significant association between 5-HTTLPR and STin2 variants and autism (Huang and Santangelo, 2008). Selective serotonin reuptake inhibitors (SSRIs) inhibit the neuronal reuptake of serotonin in the central nervous system and have shown mixed efficacy in the treatment of autistic symptoms (Moore et al., 2004). A number of studies have shown reductions in repetitive behaviors, lethargy, inappropriate speech, and improvements in the ability to relate to others, cognition, language improvement with fluoxetine (DeLong et al., 1998; Fatemi et al., 1998; Peral et al., 1999), fluvoxamine (McDougle et al., 1996b), and sertraline (Steingard et al., 1997). However, other studies have shown a lack of response with fluvoxamine (Martin et al., 2003) and citalopram (Couturier and Nicolson, 2002). 386 T.D. Folsom and S.H. Fatemi 3 Dopamine Dopamine (DA) is a catecholamine synthesized from the amino acid tyrosine and is thought to affect a wide range of behaviors and functions including cognition, motor function, selective attention, and brain-stimulation reward mechanisms (Beninger and Banasikowski, 2008; Boulougouris and Tsaltas, 2008; Cools, 2008; Fox et al., 2008). Dopamine is produced when tyrosine is hydroxylated into L-dihydroxyphenylalanine (L-DOPA), which is in turn converted to dopamine by DOPA decarboxylase (DDC). In the brain several important dopamanergic systems are of importance to autism: (1) the nigrostriatal system in which dopamanergic axons project from the substantia nigra to the neostriatum (Carlson, 2001); (2) the mesolimbic system in which dopamanergic axons project from the ventral tegmental area to the nucleus accumbens, amygdala, and hippocampus (Carlson, 2001); and (3) the mesocortical system in which dopamanergic axons project from the ventral tegmental area to the prefrontal cortex (Carlson, 2001). Despite the importance of these three systems on regulating a number of behaviors that are known to be impaired in autism, studies of DA levels in CSF, blood, and urine in subjects with autism have been inconsistent. A study of plasma and urine has revealed no differences in levels of DA or its metabolites homovanillic acid (HVA) or 3,4-dihydroxyphenylacetic acid (DOPAC) in subjects with autism when compared with controls (Minderaa et al., 1989). Two studies of HVA in CSF have found elevated levels (Gillberg et al., 1983; Gillberg and Svennerholm, 1987), while others have found no difference (Cohen et al., 1974, 1977; Winsberg et al., 1980; Ross et al., 1985; Narayan et al., 1993). Despite these findings, antipsychotic drugs, which generally function as dopamine blocking agents, have been found efficacious in treatment of autistic symptoms such as repetitive stereotyped behaviors, hyperactivity, and aggression (reviewed by Canitano and Scandurra, 2008; McDougle et al., 2008; Posey et al., 2008). Genetic studies have investigated linkages between enzymes responsible for the production of dopamine (tyrosine hydroxylase and DDC) and with dopamine receptors with autism. A study of 90 parent–offspring trios recruited in Europe found no evidence of linkage disequilibrium between two polymorphisms of DDC and autism (Lauritsen et al., 2002). Nor did they find linkage disequilibrium between haplotypes of the variants and autism (Lauritsen et al., 2002). Three studies have similarly found no link between tyrosine hydroxylase and autism (Martineau et al., 1994; Comings et al., 1995; Philippe et al., 2002). Thus far, it does not appear as though tyrosine hydroxylase or DDC are candidate genes for autism. Dopamine receptor D3 (DRD3) has also been investigated as a potential autism candidate gene. One study of autistic children found no linkage between DRD3 and autism (Martineau et al., 1994), however, in a more recent study a single nucleotide polymorphism (SNP) for DRD3 was associated with autism (de Krom et al., 2008). As the DRD3 receptor has been shown to be related to obsessive–compulsive behavior (Light et al., 2006), and liability to side effects of antipsychotic medication (Campbell et al., 1997), further study is needed to elucidate what role, if any, this receptor has in autism. Neurochemistry of Autism 387 4 Acetylcholine Acetylcholine (ACh) is a neurotransmitter found in both the central and peripheral nervous systems. In the peripheral nervous system, ACh activates muscles and in the central nervous system ACh is a neuromodulator contributing to functions including learning and memory (Kandel et al., 1995). Postmortem studies of subjects with autism have revealed abnormalities in the basal forebrain of children and adults with autism, with children having larger and more numerous cholinergic neurons and adults having smaller and less numerous cholinergic neurons (Bauman and Kemper, 1994). Cholinergic receptor (muscarinic and nicotinic) abnormalities have also been identified in brains of subjects with autism (Perry et al., 2001; Lee et al., 2002; Martin-Ruiz et al., 2004). Perry et al. (2001) found reduced [ 3 H]Pirenzepine binding to muscarinic M(1) receptors in the parietal cortex of subjects with autism and reduced [ 3 H]epibatidine binding to the α 4 and β 2 nicotinic receptor subunits in both the frontal and parietal cortices (Perry et al., 2001). Moreover, immuno- cytochemical analysis showed reduced levels of the α 4 and β 2 nicotinic receptor subunits in the parietal cortex, verifying t he binding studies (Perry et al., 2001). Similarly, a separate study showed reduced [ 3 H]epibatidine binding in the granule cell, Purkinje, and molecular layers in cerebella of subjects with autism compared with controls that was accompanied by significantly reduced α 4 subunit protein (Lee et al., 2002). In contrast, in the same regions, there was an increase in α- bungarotoxin binding to the α 7 subunit whereas there were no significant changes in muscarinic receptor subunits (Lee et al., 2002). Finally, a study by Martin- Ruiz et al. (2004) verified some of these earlier results by demonstrating reduced [ 3 H]epibatidine binding to α 4 and β 2 receptor subunits and reduced α 4 subunit mRNA in parietal cortex and increased α 7 binding and reduced α 4 subunit protein in cerebellum. Although studies have shown no differences in cholinergic enzyme mark- ers acetylcholinesterase (Perry et al., 2001) or acetyltransferase (Perry et al., 2001; Lee et al., 2002) activity in subjects with autism, acetylcholinesterase inhibitors including donepezil, rivastigmine, and galantamine have shown some promise in treating symptoms of autism. Interestingly, both donepezil and galantamine are effective in improving prepulse inhibition of the acoustic startle response in mice, suggesting that they may act as cognitive enhancers (Hohnadel et al., 2007). A pilot study using donepezil to treat children and adolescents with autism found that 50% of the subjects demonstrated significant improvement in hyperactivity and irritability (Hardan and Handen, 2002). Treatment with rivastigmine in a 12-week open-label study resulted in i ncreases in expres- sive speech and overall autistic behavior in subjects with autism (Chez et al., 2004). Treatment with galantamine has been shown to increase verbal fluency (Hertzman, 2003), improve emotional lability and inattention (Nicholson et al., 2006), and reduce anger, social withdrawal, and parent-rated irritability (Nicholson et al., 2006). These results suggest that inhibition of the breakdown of acetylcholine by acetylcholinesterase is efficacious in treating a number of symptoms of autism. 388 T.D. Folsom and S.H. Fatemi 5 GABA and Glutamate Glutamate is the primary excitatory transmitter substance in brain and spinal cord, and gamma-aminobutyric acid (GABA) is responsible for the majority of inhibitory neurotransmission in the brain (Lam et al., 2006; Carlson, 2001; Kandel et al., 1995). There are few, if any, areas in the brain that are not affected by these two substances (Lam et al., 2006; Carlson, 2001). Several reports have demonstrated abnormalities involving the glutamatergic and GABAergic systems of subjects with autism (Blatt et al., 2001; Dhossche et al., 2002; Fatemi, 2008; Fatemi et al., 2009a,b). Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme that is responsible for conversion of glutamate to GABA. In the adult brain, GAD exists in two major isoforms: GAD 65 and GAD 67 kDa proteins (Erlander et al., 1991). GAD 65 is a membrane-bound protein largely localized to axon terminals and is involved in vesicular synthesis of GABA (Laprade and Soghomonian, 1999). GAD 67 is a cyto- plasmic protein primarily localized to interneurons and is involved in nonvesicular GABA release (Reetz et al., 1991). Our laboratory has demonstrated that brain levels of GAD 65 and 67 kDa proteins were significantly decreased in cerebellum (GAD65) and parietal cortex (GAD67) in subjects with autism (Fatemi et al., 2002a). Yip et al. (2007) reported a significant decrease in GAD67 mRNA in autistic cerebellum, confirming our previous findings (Fatemi et al., 2002a). The major deficiencies in levels of GAD 65 and 67 kDa proteins in two important brain areas in autism may subserve deficiency in availability of GABA affecting important biological functions such as learning, locomotor activity, reproduction, and circadian rhythms (Soghomonian and Martin, 1998). Additionally, decreases in levels of GAD 65 and 67 kDa proteins in the autistic brain will negatively affect normal processing of visual, s omatic, locomotor, and memory information processing, and could also explain the observations of increased blood, platelet, and CSF glutamate levels in the autistic patients (Pan et al., 1999; Moreno-Fuenmayor et al., 1996; Moreno et al., 1992). Moreover, deficiency in GABA due to decreased conversion of glutamate could account for the fact that up to one third of autistic subjects suffer from seizure disorders. Binding of GABA to its receptors transduces various signals underlying various inhibitory transmissions in the brain. There are three main classes of receptors, GABA A , GABA B , and GABA C (Guidotti et al., 2005). GABA A receptors are ligand-gated ion channels that mediate GABA’s fast inhibitory action (Brandon et al., 2000). GABA A receptors are divided into multiple subunits, for example: α1–α6, β1–β4, γ1–γ4, δ, ε, π, θ, and ρ1–ρ2, which combine to form multiple GABA A receptors (Ma et al., 2005; Brandon et al., 2000). GABA B receptors are het- erodimeric, composed of the GABA B receptor 1 (GABBR1) and GABA B receptor 2 (GABBR2) subunits (Jones et al., 1998). GABA B receptors facilitate the release of neurtransmitters presynaptically generating inhibitory potentials postsynaptically (Bowery, 2000; Kuriyama et al., 2000). GABA C receptors are ionotropic, similar to GABA A receptors (Johnsoton et al., 2003) although they exhibit high GABA sensi- tivity and slow activation and deactivation kinetics (Qian and Ripps, 2008). They are Neurochemistry of Autism 389 composed of GABA ρ subunits of which there are three (ρ 1 –ρ 3 ) and are expressed primarily in the retina although they are present in other regions of the CNS (Qian and Ripps, 2008). Our laboratory has demonstrated significanlty reduced levels of GABA A and GABA B receptor protein in cerebella (GABRA1, GABBR3, GABBR1, GABBR2), parietal cortex (GABRA1, GABRA2, GABRA3, GABRA5, GABRB3, GABBR1), and prefrontal cortex (GABRA1, GABRA5, GABRA5, GABRB1, GABBR1) of subjects with autism (Fatemi et al., 2009a,b, 2010). All three brain areas have previously been implicated in the pathogenesis of autism (Bauman and Kemper, 1994, 2005). Alterations in all GABA receptors may partially explain the seizure disorders associated with autism. The occurrence of seizure disorders comorbid with autism has been estimated from 4 to 44% (Tuchman and Rapin, 2002). The pres- ence of epileptiform activity may explain cognitive deficits common to children with autism and epilepsy (Binnie, 1993); phenomena that may also occur in children with autism and epilepsy. Multiple laboratories have demonstrated altered expression of GABBR1 and GABBR2 in animal models for seizure disorders (Straessle et al., 2003; Princivalle et al., 2003a; Han et al., 2006). Moreover, expression for GABBR1A, GABBR1B, and GABBR2 are altered in the hippocampus of subjects with temporal lobe epilepsy (Princivalle et al., 2003b). 6 Oxytocin Oxytocin is a neuropeptide synthesized in the paraventricular and supraoptic nucleus of the hypothalamus. Oxytocin is released from axon terminals of the poste- rior pituitary into the bloodstream. It is also distributed to the central nervous system and oxytocin binding sites are found throughout, especially in the limbic system (Insel and Young, 2000). Oxytocin has been linked to affiliative behavior, social memory, and behavior, all of which are impaired in autism (Insel et al., 1999). It has been hypothesized that dysfunction of oxytocin and vasopresin contributes to social impairment in autism (Waterhouse et al., 1996). Animal models have shown that oxytocin plays a role in social recognition (Popik et al., 1992) and that oxytocin antagonists disrupt social memory (Engelmann et al., 1998). Oxytocin knock-out mice have been shown to be unable to recognize con- specifics and this lack of recognition is not due to general disruptions of olfaction, learning, or memory (Ferguson et al., 2000; Choleris et al., 2003). However, a single injection of oxytocin prior to the first encounter with the conspecific allowed for social memory acquisition (Ferguson et al., 2001). Plasma oxytocin has been shown to be reduced in autistic children and moreover, levels of oxytocin were correlated with social impairment (Modahl et al., 1998). A follow-up study using the same subjects found that the autistic children had higher levels of the precursor of oxytocin when compared with controls, suggesting that reduced plasma oxytocin in autistic children may be related to how oxytocin is processed (Green et al., 2001). Preliminary studies have demonstrated that infusion with oxytocin can reduce repetitive behaviors such as 390 T.D. Folsom and S.H. Fatemi need to know, repeating, self-injury, and touching (Hollander et al., 2003), and increase affective speech comprehension (Hollander et al., 2007) in subjects with autism. A number of recent studies have linked the oxytocin receptor gene (OXTR) to autism (Wu et al., 2005; Ylisaukko-oja et al., 2006; Jacob et al., 2007; Lerer et al., 2008; Yrigollen et al., 2008). OXTR expression is enhanced in brain regions associated with social behavior including the amygdala and lateral septum (Ferguson et al., 2000). OXTR knock-out mice display defects in social discrimination and demonstrate more aggression than normal mice (Takayanagi et al., 2005). Taken together, these studies suggested a potential role of OXTR in social deficits related to autism. In a study of 314 Finnish autism families a number of loci were identified as potentially conferring susceptibility to autism including 3p24-26 which includes OXTR (Ylisaukko-oja et al., 2006). A study of 57 Caucasian autism trios identified a significant association between an SNP (rs2254298) of OXTR previously associated with autism in a Han Chinese population sample (Wu et al., 2005; Jacob et al., 2007). A third study showed a significant association between SNPs (including rs2254298) and autism in an Israeli sample (Lerer et al., 2008). Moreover, an association between OXTR SNPs and IQ and Vineland Adaptive Behavior Scales (VABS) suggested that OXTR affects cognition and daily living skills in subjects with autism (Lerer et al., 2008). Finally, a link between the OXTR gene and affiliative behaviors, which are impaired in autism, has been identified (Yrigollen et al., 2008). 7 Reelin in Autism Reelin is a secreted extracellular matrix protein with serine protease activity (DeBergeyck et al., 1998) that is critically involved in guiding brain development in an orderly fashion. Changes in the level of this protein, its receptors, or downstream proteins may cause abnormal corticogenesis. Reelin binds several proteins as likely receptors, including apolipoprotein E receptor 2 (ApoER2), very-low- density lipoprotein receptor (VLDLR), and α3β1 integrin protein (D’Arcangelo et al., 1999; Hiesberger et al., 1999; Dulabon et al., 2000). Reelin binding to ApoER2 and VLDLR receptors induces clustering of the latter receptors, caus- ing dimerization/oligomerization of the adaptor protein, disabled-1 (Dab-1), on the cytosolic aspect of the plasma membrane (Strasser et al., 2004) leading to tyrosine phosphorylation of Dab-1 (Cooper and Howell, 1999), resulting in the transduc- tion of signaling pathway from the Reelin-producing cells. Embryologically, Reelin guides neurons and radial glial cells to their correct positions in the developing brain (Forster et al., 2002; Luque et al., 2003). In adults Reelin may play a role in neurotransmission as a report has indicated that Reelin has a direct effect on enhancement of long-term potentiation (LTP) in the hippocampus (Weeber et al., 2002). Two studies have demonstrated associations of polymorphisms of the RELN gene with autism (Persico et al., 2001; Zhang et al., 2002). However, four other studies have not found an association (Krebs et al., 2002; Bonora et al., 2003; Devlin et al., 2004;Lietal.,2004). Despite the lack of a clear genetic association between Neurochemistry of Autism 391 RELN and autism, protein levels of Reelin have been observed to be reduced in cerebella (Fatemi et al., 2001, 2005), frontal cortex (Fatemi et al., 2005), and blood (Fatemi et al., 2002; Lugli et al., 2003) of subjects with autism. Reduction of Reelin in frontal cortex and cerebella of subjects with autism was verified by qRT-PCR (Fatemi et al., 2005). Moreover, Reelin receptor ApoER2 mRNA was increased in frontal cortex and cerebella of subjects with autism and downstream signaling molecule Dab-1 mRNA was decreased in the same brain areas (Fatemi et al., 2005) suggesting impairments in the Reelin signaling system. These impairments may be partly responsible for the structural and cognitive deficits observed in autism. 8 Conclusion Autism is a heterogeneous disorder with no definitive etiology. Brain pathology, gene expression, and neurochemical dysfunction of various neurotransmitter signaling systems including serotonin, dopamine, acetylcholine, GABA and glutamate, and oxytocin suggest a role of neurotransmitter systems in the pathology of autism. Pharmacological treatments focus on reduction of various symptoms of autism and SSRIs, antiacetylcholinesterases, and infusions of oxytocin, have all shown some efficacy. Acknowledgments Grant support by National Institute of Child Health and Human Development (#5R01HD052074-01A2 and #3R01KD052074-03S1) to SHF is gratefully acknowledged References Acosta MT, Pearl PL (2003) The neurobiology of autism: new pieces of the puzzle. Curr Neurol Neurosci Rep 3:149–156 Amara SG, Pacholczyk T (1991) Sodium-dependent neurotransmitter reuptake systems. 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Nature 396:674–679 . acetylcholinesterase inhibitors including donepezil, rivastigmine, and galantamine have shown some promise in treating symptoms of autism. Interestingly, both donepezil and galantamine are effective in improving prepulse. demonstrating reduced [ 3 H]epibatidine binding to α 4 and β 2 receptor subunits and reduced α 4 subunit mRNA in parietal cortex and increased α 7 binding and reduced α 4 subunit protein in cerebellum. Although. [ 3 H]Pirenzepine binding to muscarinic M(1) receptors in the parietal cortex of subjects with autism and reduced [ 3 H]epibatidine binding to the α 4 and β 2 nicotinic receptor subunits in both the

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