**4. Serotonin**

Serotonin is a neuromodulator which acts as a developmental signal [65]. Serotonin is synthesized by the enzyme triptophanhidroksilase which convert triptpohan to 5-hydroxytryptophan, and decarboksilation at the end [66]. Serotonin neurotransmitter system has critical role in the regulation of crucial steps of neuronal development such as cell proliferation, differentiation, migration, apoptosis synaptogenesis, neuronal and glial development [67, 68]. Serotonin system in the prefrontal cortex and temporal cortex regulates GABAergic inhibition, therefore it has played a role in the regulation of many aspects of cognitive functions [69].

stratedhigher serumglutamate levels inindividualswithautism[46].Increasedglutamate level probably connected with diminished GAD enzyme level [47, 48, 49]. This diminish also explain reduction in GABA transmission [50]. First study was done by Shimmura has illustrated higher serumglutamate levels andlower glutamine levels [51]. Secondly Shimmura et al.[52]hasdone another study they researchedbrain tissue from 7 postmortem ASDpatients,they found higher levels of glutamate and glutamine levels at anterior cingulate cortex, interstingly levlels of glutaminase, glutamine synthase, and GAD were normal. As mentioned above ASD patients have high incidence of epilepsy, this is due to increase in glutamatergic activity [53, 54].

Animal models and conducted clinical studies in ASD subjects support hyperglutamatergic hypothesis. Silverman et al. [55] is conducted a study on ASD core symptoms observed mice model and found that GRN-529 (allosteric modulators of mGluR5 receptor) ameliorated all core symptoms of ASD. Another study conducted with AMPA receptor agonist (Ampakin) relieved symptoms of respiratory system on mice model with Rett syndrome [56]. Lamotrigine, which reduce glutamate transmission, has improved communication skills, socialization and behavior problems in 28 children diagnosed with ASD [57]. Ketamine, an NMDA receptor antagonist, has been shown to have a positive impact on focused attention in ASD cases [58]. Another NMDA receptor antagonist, memantine, significant improvement was observed on learning, language skills and in the areas of socialization in patients with ASD [59]. Recently, a randomized controlled study carried out, the memantine and risperidone receiving group were compared to placebo and risperidone receiving group, at the 10th week of treatment, memantine and risperidone received group better recovered compared to only risperidone received group in terms of the irritability, stereotypies and hyperactivity symptoms [60]. Recently, non-invasive brain imaging techniques such as magnetic resonance spectroscopy has enabled measurment of glutamate levels in brain tissue. Since first study was published in 2006 to date there were 15 studies done and conflicting results have been obtained [37]. In some studies, the anterior cingulate cortex [61] and auditory cortex [62] areas glutamate levels was increased compared to healthy controls, while in others there was no difference, and in

Some researchers thought these two hypotheses related to glutamatergic system are not completely opposite, some spesific cortical areas has increased excitatory / inhibitory ratio

As a result, it is not clear yet whether the ASD individuals hyper or hypoglutamatergic, but it is clear that there is dysfunction in the glutamatergic system. New investigations has focused more in hyper-glutamatergic state and efforts are directed at glutamate receptor antagonismin order to develop new therapeutic agents. A better understanding of the glutamatergic system

Serotonin is a neuromodulator which acts as a developmental signal [65]. Serotonin is synthesized by the enzyme triptophanhidroksilase which convert triptpohan to 5-hydroxy-

the rest lower glutamate levels was observed [63, 64].

18 Autism Spectrum Disorder - Recent Advances

**4. Serotonin**

whereas in other regions, this ratio could turn opposite [44].

agents in the future will contribute to enlight ASD pathogenesis.

Serotonin plays an important role in the development of social skills during gestational period and early childhood. Inadequate stimulation of serotonin in the early stages of life, can lead to the unpreventable abnormalities in serotonin metabolism in subsequent period of life. These defect may cause permanent problems in serotonin metabolism in people who have been deprived serotonin effects necessary for the brains especially early developmental stages of life. This is why, adequate levels of serotonin are necessary for the development of close relationships and social skills in the early stages of life [70]. Social skills and behavior have been shown to be associated with hippocampal neurogenesis in ASD individuals and because of that hippocampal abnormalities are found frequently [71]. Serotonin play a central regu‐ lating role in serotonin dependent neurogenesis activity in the hippocampus [72].

Pathophysiology of ASD has two main hypothesis for serotonin neurotransmitter systems, just like glutamate hypothesis. One widely accepted for a long time and confirmed for many times is hyperserotonin state and while the other one is hyposerotonin hypothesis which became prominent in recent years [66]. Two main findings of hyperserotonin hypothesis in patients with ASD are increased blood serotonin levels (my hiperserotone) and decreased brain serotonin levels [66]. The presence of hyperserotonemia in 25 to 50% of individuals with ASD is important to showing they may have abnormalities in the serotonergic pathway [73, 74,75].

Furthermore, first-degree relatives of individuals with ASD found to have hyperserotonemia, as well as parents of these kids more often showed the presence of serotonin associated psychiatric disorders, such as depression and obsessive-compulsive disorder [74, 76]. Other supportive evidence, brain serotonin level decreased and exacerbation of many repetitive behavior was observed (such as spinning, stepping, self-hit and shoot) with tryptophan poor diet (low-tryptophan diet) [77]. Serum levels of tryptophan to large neutral amino acid ratio was shown to be decreased in children with ASD. This rate is an indicative of presence of tryptophan for serotonin synthesis in the brain and this lower ratio demonstrate low trypto‐ phan usability which might suggest one of the mechanisms associated with serotonergic dysfunction in ASD [78]. Another study demonstrated, after L-5-hydroxytryptophan admin‐ istration young people with ASD, their blood serotonin levels increased, whereas in control group no difference was seen [79].

Severity of at least one specific behavioral problem in ASD is reported to be associated with 5HT1D receptor sensitivity [80]. Various studies have reported controversial results regarding association of serotonin transporter gene in ASD. In contrast, in accordance with the data regarding the transfer of serotonin transporter gene polymorphic alleles associat‐ ed with the findings of the degree of the social and communicative deficits, these alleles instead of being risk factor for ASD they might change the severity of clinical presenta‐ tion in autistic children [75].

Shown correlation between ASD and serotonin transporter gene and found mutations in genes encode rate-limiting enzyme in the catabolism of L-tryptophan such as 2,3 dioxygenase gene is thought to be responsible for increased serotonin levels [81]. There might be defect in the development of the serotonergic system in patients with ASD. Normally, the serotonin neurotransmitter system follows a pattern of age-related development, for example, develop‐ mental studies of serotonin receptor binding in monkeys showed that increment during infancy and throughout childhood, a prepubertal peak, and eventually slowly reduction during adolescence and early adulthood [82]. In humans at 6 year of age serotonin receptor binding is higher than neonatal period or 13-14 year of age [83]. This dynamic changes are impaired in ASD, at the beginning of childhood low serotonin levels are observed compared to normal baseline, but steadily increased from 2 to 15 years of age and reaches higher than adult levels [84, 85]. In various animal models when effect of higher levels of serotonin investigated particılarly in the development of somatosensory system, the deterioration in the formation of thalamo-cortical sensory circuits were observed [86]. Recently "ASD is a hypo‐ serotonergic condition" hypothesis is worth to discuss. In a study of volunteer postmortem brain tissue of ASD patients examined, and the increase in number of serotonergic axons were observed [87].

This situation cannot be explained by the hypothesis of compensatory mechanisms which expected to result reduction of serotonergic axons in hyperserotonergic state [88]. In men with ASD, in one side of the brain of frontal region and thalamus, typically synthesis of serotonin was reduced, in opposite side of the brain of cerebellum, and dentate nucleus serotonin has been shown to be increased [70].

Several PET and SPECT studies in individuals with ASD has shown serotonin transporter binding amount decreased significantly in various brain regions (frontal cortex, cingulate, thalamus, etc..) [89, 90]. Other study was exhibited that low levels of blood serotonin in mothers of children with ASD compared to normal developing children's mother [91]. In another study, individuals with ASD were shown to have low levels of gene responsible for synthesis of serotonin [92]. Serotonergic drugs, the main symptoms of ASD respond less to treatment, but some are partially effective in the symptomatic treatment of patients with autism. These drugs include selective serotonin reuptake inhibitors (selective serotonin reuptake inhibitör=SSRI), 5-HT 2A receptor antagonists, tricyclic antidepressants and receptor antagonists (dopamin/5- HT) mix.

Mechanism of action of these treatments are unknown, but they are thought to act on the developmental defects in serotonergic pathways such as serotonin synthesis, catabolism, and transport-related dynamic abnormalities [93, 94].

As a result, the highest level of evidence for ASD relationship with monoamines is the serotonergic system. Hyperserotonemia in peripheral blood in individuals with ASD, despite the presence of opposite results, has been shown to be present in many studies. Low levels of serotonin in the brain tissue is the common finding of hyposerotonergic and hyperserotonergic hypothesis. Future studies will enlight reson for lower serotonin levels in the brain tissue and will open new horizons both for diagnosis and treatment.
