[3H]-Flunitrazepam-labeled Benzodiazepine Binding Sites in the Hippocampal Formation in Autism: A Multiple Concentration Autoradiographic Study

Abstract

Increasing evidence indicates that the GABAergic system in cerebellar and limbic structures is affected in autism. We extended our previous study that found reduced [(3)H]flunitrazepam-labeled benzodiazepine sites in the autistic hippocampus to determine whether this reduction was due to a decrease in binding site number (B (max)) or altered affinity (K (d)) to bind to the ligand. Quantitation of hippocampal lamina demonstrated a 20% reduction in B (max) indicating a trend toward a decreased number of benzodiazepine binding sites in the autistic group but normal K (d) values. A reduction in the number of hippocampal benzodiazepine binding sites suggests alterations in the modulation of GABA(A) receptors in the presence of GABA in the autistic brain, possibly resulting in altered inhibitory functioning of hippocampal circuitry.

Microtransplantation of neurotransmitter receptors from postmortem autistic brains to Xenopus oocytes

“…An increased number of neurons in the cerebral cortex has also been described (24). Furthermore, ligandbinding studies in postmortem tissues have shown that GABA receptors containing the benzodiazepine ligand-binding site are substantially reduced in the hippocampus (5,9) and that AMPA1 receptors are reduced in the cerebellum (7).…”

“…The autism spectrum disorder is a multifaceted syndrome, probably due to many different causes (2)(3)(4). Although these causes are largely unknown, genetic and biochemical studies strongly implicate the GABA and glutamate neurotransmitter receptors, which are, respectively, the principal inhibitory and excitatory receptors in the mammalian brain, including that of humans (5)(6)(7)(8)(9)(10)(11). Despite the immense importance that neurotransmitter receptors have for brain functioning, relatively little is known about the functional properties of receptors of the human brain; almost nothing is known about those of the autistic brain.…”

Non-Invasive Evaluation of the GABAergic/Glutamatergic System in Autistic Patients Observed by MEGA-Editing Proton MR Spectroscopy Using a Clinical 3 Tesla Instrument

“…Recently, the downregulation or alteration of both the GABA A and GABA B receptors in subjects with autism was reported (Fatemi et al 2008(Fatemi et al , 2009, and an autoradiographic study using the [3H]flunitrazepam-labeled benzodiazepine site also suggested there is an alteration in the modulation of the GABA A receptors in the autistic brain (Guptill et al 2007). This accumulating evidence of GABA receptor abnormality indicates that the GABAergic system in the autistic brain is affected.…”

GABA and Glutamate Receptors of the Autistic Brain

“…Blatt et al (2001) reported a reduced binding of benzodiazepines and muscimol in the hippocampus of autistic brains, suggesting a decrease in the number of GABA A receptors. Posterior studies using different concentrations of [H 3 ]flunitrazepan showed that the decrement of benzodiazepine binding was due to reductions of binding sites with no changes in the binding affinity of the receptors (Guptill et al, 2007). Western blot analyses of four GABA A subunits (1-3 and 3) showed reductions of all subunits in parietal cortex, of 1 in frontal cortex and of 1 and 3 in cerebellum of post-mortem autistic brains (Fatemi et al, 2009).…”