ABSTRACT
Several lines of evidence suggest that schizophrenia is associated with deficits in glutamatergic transmission at the N-methyl-d-aspartate (NMDA) receptors. Glycine is a NMDA receptor co-agonist, and extracellular levels of glycine are regulated in the forebrain by the glycine type-1 transporters (GlyT-1). GlyT-1 inhibitors elevate extracellular glycine and thus potentiate NMDA transmission. This mechanism represents a promising new avenue for the treatment of schizophrenia. Here, the recently introduced positron emission tomography radiotracer [11C]GSK931145 was used to quantify the relationship between occupancy of GlyT-1 by a GlyT-1 inhibitor, Org 25935, and its impact on spatial working memory performances in rhesus monkeys. The effect of Org 25935 on working memory was assessed both in control conditions and during a state of relative NMDA hypofunction induced by ketamine administration, at a dose selected for each animal to reduce task performance by about 50%. Under control conditions, Org 25935 had no effect on working memory at GlyT-1 occupancies lower than 75% and significantly impaired working memory at occupancies higher than 75%. Under ketamine conditions, Org 25935 reversed the deficit in working memory induced by ketamine and did so optimally in the 40-70% GlyT-1 occupancy range. The results confirm the efficacy of this mechanism to correct working memory deficits associated with NMDA hypofunction. These data also suggest the existence of an inverted-U dose-response curve in the potential therapeutic effect of this class of compounds.
Subject(s)
Brain/physiology , Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Memory, Short-Term/physiology , Spatial Memory/physiology , Animals , Benzamides , Brain/diagnostic imaging , Carbon Radioisotopes , Central Nervous System Agents/pharmacokinetics , Central Nervous System Agents/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Female , Glycine Plasma Membrane Transport Proteins/metabolism , Ketamine/pharmacology , Macaca mulatta , Male , Memory, Short-Term/drug effects , N-Methylaspartate/metabolism , Neuropsychological Tests , Positron-Emission Tomography , Radiopharmaceuticals , Spatial Memory/drug effects , Tetrahydronaphthalenes/pharmacokinetics , Tetrahydronaphthalenes/pharmacologyABSTRACT
Tuberous sclerosis complex (TSC) is a multisystem syndrome classically associated with the occurrence of focal brain dysplasias. We used structural magnetic resonance imaging to test for neuroradiological abnormalities in TSC (tubers, white matter lesions, and subependymal nodules) and to explore the relationships between these lesions and computational morphometric abnormalities of gray and white matter distribution. We tested memory function in TSC and investigated the relationship between memory function and both morphometric variation and lesion load. Patients demonstrated deficits bilaterally in volume of subcortical gray matter regions including thalamus, basal ganglia, insula, and cerebellum, as well as white matter deficits bilaterally in intrahemispheric tracts. Morphometric deficits could not be explained as local effects of lesions. Patients demonstrated deficits in executive working memory and recall memory, sparing recognition. Structure-function mapping showed long-term and working memory function was positively correlated with gray matter density (in thalamus, caudate nucleus, and frontal cortex) but not with lesion load. The neuroanatomical endophenotype of TSC is more extensive than previously recognized and comprises abnormalities in the distribution of gray and white matter in addition to classical lesions. Normal intelligence quotient patients with TSC show a profile of long-term and working memory impairment that is related to gray matter deficits in thalamus and basal ganglia components of fronto-striatal circuits.
Subject(s)
Brain/pathology , Brain/physiopathology , Memory Disorders/pathology , Memory Disorders/physiopathology , Tuberous Sclerosis/pathology , Tuberous Sclerosis/physiopathology , Adult , Female , Humans , Magnetic Resonance Imaging , Male , Memory Disorders/etiology , Neuroanatomy/methods , Statistics as Topic , Tuberous Sclerosis/complicationsABSTRACT
BACKGROUND: Neuroimaging studies of tuberous sclerosis complex (TSC) have previously focused mainly on tubers or subependymal nodules. Subtle pathological changes in the structure of the brain have not been studied in detail. Computationally intensive techniques for reliable morphometry of brain structure are useful in disorders like TSC, where there is little prior data to guide selection of regions of interest. METHODS: Dual-echo, fast spin-echo MRI data were acquired from 10 TSC patients of normal intelligence and eight age-matched controls. Between-group differences in grey matter, white matter and cerebrospinal fluid were estimated at each intracerebral voxel after registration of these images in standard space; a permutation test based on spatial statistics was used for inference. CSF-attenuated FLAIR images were acquired for neuroradiological rating of tuber number. RESULTS: Significant deficits were found in patients, relative to comparison subjects, of grey matter volume bilaterally in the medial temporal lobes, posterior cingulate gyrus, thalamus and basal ganglia, and unilaterally in right fronto-parietal cortex (patients -20%). We also found significant and approximately symmetrical deficits of central white matter involving the longitudinal fasciculi and other major intrahemispheric tracts (patients -21%); and a bilateral cerebellar region of relative white matter excess (patients +28%). Within the patient group, grey matter volume in limbic and subcortical regions of deficit was negatively correlated with tuber count. CONCLUSIONS: Neuropathological changes associated with TSC may be more extensive than hitherto suspected, involving radiologically normal parenchymal structures as well as tubers, although these two aspects of the disorder may be correlated.
