**2. GABA**

In order to maintain function and homeostasis of Central Nervous System (CNS) the balance between excitation and inhibition of neurons is very important. Main inhibitory neurotrans‐ mitter in the brain is gamma amino butyric acid (GABA) [5]. GABA is synthesized from glutamate by the enzyme glutamic acid decarbosilase (GAD) [6]. This enzyme has two isoforms known as GAD67 and GAD65, these are encoded by GAD1 and GAD2 gene. These enzymes different from each other in terms of the intracellular localization, expression, and enzymatic activity [7]. After GABA sythesized, it is taken to the vesicle by vesicular GABA transporter (VGATs) [8]. GABA is released to synaptic space under influence of Action Potential (AP) and binds to the GABAA and GABAC iyonotrophic receptors or metabotrop‐ ic GABAB receptors [9]. The activity of GABA that is released to the synaptic space is ended by GABA transporters which are located at cell membrane (GAT) [10]. Finally GABA that

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is taken to the inside cell furtherly degrades by the transaminase or succinate semialde‐ hide dehidrogenase enzymes [9].

GABA has a key role in the regulation of early developmental stages of cell migration, neuronal differentiation and stages of maturation [11]. Besides, formation of GABAergic system has a critical role in migration of GABAergic neurons and formation of glutamer‐ gic system mediated excitatory processes that regulate cortical inhibitory system [12]. Therefore, it is not suprising that especially in ASD and in many neurodevelopmental disorders GABAergic system is the main responsible [13, 14]. In addition, the high prevalence of epilepsy in patients with autism have made it worth to investigate GABA neurotransmitter system in individuals who has ASD [15].

Neurochemical abnormality that postulated to be associated with pathophysiology of ASD is the reduction in the expression of GAD65 and GAD67 which cause suppression of GABAergic inhibition [16]. Fatemi and his colleagues [17], in the cerebellum and parietal cortex of patients has shown significantly decrease in two isoforms of the rate-limiting enzyme which are responsible for the conversion of glutamate to GABA. Detection of low platelet GABA levels in children with ASD [18] and postmortem studies that illustrtaed significant reduction in GABAA and GABAB receptor subunit in various brain regions [19, 20] support the widespread dysfunction of GABAergic system in patients with ASD. Reduced production or signaling of GABA cause hyperexcitability state and leads to cognitive dysfunction [21]. Deletional mutations of genes encoded by chromosome 15q11-q13 which is some of the GABAA receptor subtype unites (GABRB3, GABRA5 and GABRG3) might be cause of reduction in GABAergic transmission, and these mutations have been suggested to be a risk factor ASD [14]. Also, many of the candidate genes associated with ASD are expressed in interneurons [22]. Antiepileptic agents, especially benzodiazepines has been used in ASD and epilepsy coexisted patients and they have shown to improve socialization and communication skills, though, in some cases, they lead to increased anxiety and aggression, because of this, the information mentioned above is not clear yet [23,24]. Lemonier and Ben-Ari [25] sugeested that the inhibition of Na / K / Cl transporter (NKCC1) lead intracellular increased Cl levels, so the GABAergic transmis‐ sion will change depolarization to the hyperpolarization and in five ASD cases they get positive results after the treatment with NKCC1 inihbitor bumetanide. Then they carried out double blind randomized controlled clinical trial of bumetanide for treatment of ASD for 3 months of period in 54 patients, the results has shown to provide a significant improvement of ASD symptoms [26]. In utero exposure to valproate in mice model, has caused dissappearance of swicth between GABA excitation / inhibition and this problem has shown to lead the devel‐ opment of chronic chlorine deficits and autistic-like behavior [27]. Ion channels mutated mouse model which led to the reduced GABAergic transmission, and the corelation between ASD symptoms and reduced GABAergic transmission level and with benzodiazepine treatment autistic-like behavior to has shown to decrease [28].

As a result of animal model publications and studies conducted in patients with ASD has confirmed the hypothesis of "decreased GABAergic transmission in ASD patients". In future studies, to develop a new therapeutic agents, and to even prevent the disease focus should be directed on the GABA neurotransmitter system.
