Serotoninergic, GABAergic, and glutamatergic pathways
Serotoninergic, GABAergic, and Glutamatergic pathways
Serotonin platelet levels are elevated in 25-33% of people with autism, which indicates that serotonin may be associated with the pathophysiology of autism.3 One group, Chugani et. al. has demonstrated that there are developmental differences in serotonin synthesis capacity between those with autism and those without. Global brain values for autistic children, non-autistic children, and epileptic children without autism were obtained and trajectories were plotted for serotonin synthesis capacity. It was found that for non-autistic children, serotonin synthesis capacity was greater than 200% of adult capacity until 5 years, when capacity then started declining until it reached adult values. For autistic children, serotonin synthesis capacity gradually increased between 2-11 years of age to 1 and a half times the normal values of an adult. Some analysis have showed a correlation in the differences in serotonin synthesis with language skill acquisition12.
Pharmacological and knock-out experiments with mice show that serotonin can also affect synaptogenesis. There is transient serotonergic innervation of the primary sensory cortex between postnatal days 2-14 during the period of synaptogenesis in the rat cortex. There is transient expression of high-affinity serotonin transporter and vesicular monoamine transporter by glutamergic thalamocortical neurons. Thalamo-cortical neurons take up and store serotonin during this period but do not synthesis the neurotransmitter. Depletion of serotonin stores delays the development of the barrel fields of the rat somatosensory cortex and decreases the size of barrel fields. Too much serotonin results in increased tangential arborization of these axons resulting in the blurring of boundaries between cortical barrels.
There is also evidence that changes in the serotonin receptor 5HT1A can affect the brain regions that are abnormal in autism.2Although the exact relationship between serotonin and autism is not known, research suggests that the change in thalamo-cortico connections may result from several types of 5-HT transporters, a decreased central response to 5-HT, or diminished binding to 5-HT receptors.3
Abnormalities in the GABAergic system have been found the platelets of all of the autistic children in one study, which makes some researchers hypothesize that the elevated plasma GABA levels result because of hyposensitivity of a subset of GABA recepters. Presynaptic cells increase GABA release to compensate for the subsets' decreased sensitivity, but this in consequently results in increased post-synaptic activation of other normal GABA receptor subtypes. In a study by Blatt et. al6, the hippocampal density and distribution of neurotransmitter receptors from the GABAergic, serotonergic, cholinergic, and glutamatergic systems in autistic patients and controls were and found that only the GABAergic receptor system was significantly reduced in autism.4
The concentrations of the GABAergic subunits change across development. For example, α1 subunits are expressed at a low level at birth and increases during the first week after birth, while α2 subunit expression decreases steadily. During early development, GABA actually causes depolarization of the cells because there is a relatively high concentration of intracellular Cl- ions. It is thought that the excitation is important for plasticity, synaptic connections, and establishing neural connections. This view is supported by experiments which showed that primary cultures of several embryonic and neonatal brain tissues, GABA has various neurotropic effects including the promotion of neurite extension, synaptogenesis, and the synthesis of its own receptors. Additionally, excitatory GABAergic interneurons generate huge depolarizing potentials which can cause primitive network-driven patterns of electrical activity in all developing circuits.5 During maturation though, GABA is an inhibitory neurotransmitter. It is not known in humans when this switch happens.
GABAergic neurons, in contrast to most cortical neurons which migrate radially during development, migrate tangentially within the intermediate zone. GABA receptor activation in the developing cortex could modulate the rate of cell migration.
There are decreased GABA receptors and a decrease in benzodiazepine binding sites in the anterior cingulate cortex in autistic patients as compared to typically developing controls. These findings may result from increased GABA innervation and/or release which disturbs the balance of excitation/inhibition of principle neurons and their output to other targets in the limbic system.7
Gabaergic interneurons are at the core and periphery of minicolumns.11
Glutamate is the principal excitatory neurotransmitter in the brain. Glutamate receptors and glutatamate transport proteins are important in neuron migrate, differentiation, dendritic and synpatic development. Studies have demonstrated that oscillations of Ca2+ in granule cell regulates neuron migration. Testosterone, glutamate and kainate/AMPA and mGluR can modulate Ca2+ oscillations. The Glutamate receptor system consists of ionotropic receptors NMDA, AMPA, kainate and metabotropic receptors of mGluR types. The GluR system is complicated with a complex set of subunits and receptor types. The particular patterns of subunit assembly in various GluR produces regional differences in brain's response to glutamate stimulation.9, 10 Extracellular glutamate is extremely toxic, so a complex system has developed to prevent extracellular glutamate accumulation. Gene association studies have associated GluR6, a glutmate receptor, with Autism. GluR6 controls a member of the ionotropic receptor kainate family, which affects brain development. Another study has linked a sequence on chromosome 11p12-13 to glutamate transport proteins. GluR8 and GluR2 as well as glycine receptors (GLRA3 and GLRB) abnormalities have also been detected in autistic patients. Additionally, post mortem analysis of the brains of patients with autism have shown that expression levels of various proteins related to the Glutamate pathway were elevated.1 Studies have shown an elevation in blood and cerebral spinal fluid glutamate levels and microglial and astrocyte activation, both of which are major sites of glutamate release.8