Postnatal maturation of human GABA receptors measured with positron emission tomography

During brain development in nonhuman primates, there are large changes in GABA,receptor binding and subunit expression. An understanding of human GABAA receptor ontogeny is highly relevant in elucidating the pathophysiology of neurodevelopmental disorders in which GABAergic mechanisms play a role as well as in understanding differences that occur during development in the pharmacology of drugs acting on this system. We have measured age-related changes in the brain distribution of the GABA(A) receptor complex in vivo using positron emission tomography (PET) in epileptic children under evaluation for surgical treatment. PET imaging was performed using the tracer [C-11]flumazenil (FMZ), a ligand that binds to ex subunits of the GABA, receptor. FMZ binding was quantified using a two-compartment model yielding values for the volume of distribution (VD) Of the tracer in tissue. Ah brain regions studied showed the highest value for FMZ VD at the youngest age measured (2 years), and the values then decreased exponentially with age. Medial temporal lobe structures, primary visual cortex, and thalamus showed larger differences between values for age 2 years and adults (approximately 50% decrease) than did basal ganglia, cerebellum, and other cortical regions (25-40% decreases). Furthermore, subcortical regions reached adult values earlier (14-17.5 years) than did cortical regions (18-22 years). The ontogeny data of FMZ VD from children may contribute to understanding regional differences in synaptic plasticity as well as improve rational therapeutic use of drugs acting at the GABA(A) receptor in the pediatric population.