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Further studies of GABA and Glutamate imbalances in autism are important challenges for future research

In the study by Khalifa et al. in this issue of Acta Paediatrica (1), levels of the excitatory neurotransmitter glutamate were analysed in a clinical sample of young children aged 3–10 years with autism spectrum disorders (ASD). The 30 children were randomly selected from the ASD Outpatient Clinic at the Abou El-Reesh Hospitals, Cairo University and compared to 30 randomly selected controls, without any mental disorders or major medical illnesses, whose siblings were attending another outpatient clinic at the hospital. The prevalence of ASD has been the subject of many studies, and, as the authors report, many of which have reported a dramatic increase during the last decade. A Swedish study (2) reported that considerably fewer ASD symptoms now seemed to be required for a clinical diagnosis of ASD, particularly after the preschool years. These findings suggest that increases in ASD diagnoses could be partly due to how ASD is diagnosed. The increased level of serum glutamate that was found by Khalifa et al. (1) is interesting and in line with other studies of serum glutamate in children with autism that they refer to and has clinical and further research implications. As the authors point out, glutamate is one of the major excitatory neurotransmitters in the human brain and plays a significant role in brain development, cell migration, synapse induction and cell differentiation. It is also involved in a wide range of neural and cognitive functions, such as learning and memory. Although glutamate does not cross the blood–brain barrier readily, levels of glutamate in blood and cerebrospinal fluid have been positively correlated in humans, suggesting that peripheral glutamate levels can reflect the glutamate level in the brain (3). In an early study (1992) (4), the concentration of glutamate, but of no other amino acid, was markedly elevated in the cerebrospinal fluid of patients with Rett syndrome, a genetic disorder characterised by the loss of functions and in many cases a period with autistic features. Attempts to understand the pathobiology of the glutamatergic system have led to new investigational treatments for ASD. The potential implications of modulating the glutamatergic system while treating ASD, by using specific drugs that affect glutamatergic receptors, have been explored in preclinical and clinical studies. These have specifically targeted the NMDA receptors (agonists and antagonists), the AMPA/kainate receptors (antagonists) and metabotropic glutamate receptor 5 (mGluR5) (antagonists) and other mechanisms in the glutamatergic system (5). However, despite the potentially encouraging preliminary findings of clinical trials using glutamate, there are several limitations. These are mainly associated with the fact that ASD is a very heterogeneous disorder with many potential aetiologies, including those where a glutamatergic dysfunction might not play a key role in the pathophysiology (5). There is a growing interest in this area, and studies have indicated an imbalance in excitatory (glutamatergic) and inhibitory c-aminobutyric acid (GABAergic) neurotransmission in ASD (1). Although GABA is best known as an inhibitory neurotransmitter, it can be either inhibitory or excitatory, depending on intraneuronal (Cl ), which is modulated by two isoforms of the cation-Cl cotransporter family. These are NKCC1, an isoform of the Na-K-2Cl cotransporter, and KCC2, an isoform of the K-Cl cotransporter. NKCC1 transports Cl , along with Na and K, into the neuron, which increases (Cl ) leading to depolarisation (excitatory state) on the opening of Cl channels, such as GABA-A receptors. KCC2 transports Cl , along with K, out of the neuron, which decreases (Cl ) leading to hyperpolarisation (inhibitory state) with Cl channel opening (6). NKCC1 is widely distributed throughout the body and is also found in neurons (6). Normally, adult neurons have low intracellular chloride levels underlying the GABAergic inhibitory drive. In contrast, there are high chloride levels and concomitant excitatory GABA actions in a wide range of pathological conditions. Reducing GABAergic inhibition produces neuronal hyperexcitability, and can lead to deleterious neurological and psychiatric sequelae, including ASD (7). These observations have raised considerable interest in the development of pharmacological treatments that restore physiological (Cl ) levels and GABAergic inhibition in pathological conditions (7,8). Based on animal studies of autism, revealing that the NKCC1 chloride-importer inhibitor bumetanide restores physiological chloride levels and enhances GABAergic