GABA as the pallidothalamic neurotransmitter: implications for basal ganglia function

GABA levels, high affinity GABA uptake and glutamic acid decarboxylase levels are reduced in rat ventroanterolateral thalamic nucleus after destruction of the entopeduncular nucleus with kainic acid. This is strong evidence that GABA is an entopedunculothalamic neurotransmitter. The striatoentopeduncular pathway is also GABAergic. Thus the function of the corpus striatum may be to disinhibit the thalamus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24459/1/0000733.pd

NMDA, AMPA, and benzodiazepine binding site changes in Alzheimer's disease visual cortex

Quantitative receptor autoradiography was used to measure the laminar distribution of [3H]glycine and [3H]glutamate binding to the N-methyl-D-aspartate (NMDA) receptor complex, [3H]D,L-a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) binding to the AMPA receptor, and [3H]flunitrazepam binding to the benzodiazepine (BDZ) receptor in three areas of visual cortex in control and Alzheimer's disease (AD) postmortem human brains (primary or striate visual cortex, visual association cortex, and higher-order visual association cortex, corresponding to Brodmami Areas 17, 18, and 21, respectively). In Area 17, binding to the NMDA, AMPA, and BDZ receptors was not significantly altered in the AD brains (except in layer VI for [3H]glycine and layer III for [3H]AMPA, where binding was reduced in the AD brains). Ligand binding to the two EAA receptors in Area 18 was, however significantly reduced in the AD brains (layers I through III for [3h]glycine and layers III through VI for [3H]AMPA). In Area 21, binding to both the NMDA and BDZ receptors but not to the AMPA receptor, was significantly reduced in almost all laminae of the AD brains (layers I through VI for [3H]glycine and layers I through V for [3H]flunitrazepam). This hierarchical pattern of laminar binding loss with increasing complexity of association visual cortices is consistent with the increasing numbers of neurofibrillary tangles found in those areas, implicating NMDA and BDZ receptor bearing cells in AD neuropathology. AMPA receptor losses do not parallel the pathology, suggesting that AMPA receptors are not directly correlated with the pathology.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30715/1/0000361.pd

Quantitative autoradiography of hippocampal GABAB and GABAA receptor changes in Alzheimer's disease

GABAB and GABAA receptors were examined by quantitative [3H]GABA autoradiography in postmortem human hippocampus from 6 histopathologically verified cases of dementia of the Alzheimer type (DAT) and 6 normal controls. Significant decrements in the Bmax for both types of GABA receptors were observed in DAT hippocampus as compared to normal controls. No significant differences in Kd values were revealed. As compared to controls, DAT hippocampus exhibited fewer GABAB receptors in stratum moleculare of the dentate gyrus, stratum lacunosum-moleculare and stratum pyramidale of CA1. Significant loss of GABAA receptors in DAT hippocampus was also observed in the CA1 pyramidal cell region. These changes could not be correlated with differences in age nor in postmortem delay between the two groups. These findings may reflect the neuronal pathologies in CA1 region, in dentate gyrus, and in projections from the entorhinal cortex which are associated with the memory impairment in DAT.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26473/1/0000008.pd

Computer-assisted estimates of lesion sizes and shrinkage in denervated areas from receptor autoradiograms using a digitizing tablet

Area measurements taken from receptor autoradiograms were employed to estimate the size of striatal kainate lesions and the amount of shrinkage in deafferented projection areas. There was no significant difference in the size of substantia nigra (SN) on the denervated side as compared to the intact side one week and one month after unilateral striatal lesions. Although there was no change in the size of globus pallidus (GP) on the lesioned side one week after the lesion, there was a 17% shrinkage one month after the lesion. At 3-4 months after the lesion, the amount of shrinkage was 19% in SN and 16% in GP.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24901/1/0000328.pd

The globus pallidus receives a projection from the parafascicular nucleus in the rat

Study of the afferents of the rat globus pallidus (GP) with Fluoro-gold, a retrograde tracer, revealed retrogradely labeled neurons in the ipsilateral parafascicular nucleus of the thalamus (PF), a previously undescribed afferent of the rat GP. We used the anterograde tracer, Phaseolus vulgaris-leucoagglutinin (PHA-L), to confirm and extend our findings. After injections of PHA-L in the PF, labeled fibers with varicosities and terminal specializations were observed in the ipsilateral GP. The topographical organization of the projection is such that lateral and ventral PF neurons project preferentially to respective parts of the GP, and medial PF neurons project primarily to the ventral GP. There were very few labeled fibers seen in the dorsal or medial GP. The presently described projection from the PF to the GP provides an additional route for the PF to influence basal ganglia circuitry.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29231/1/0000286.pd

Glutamate dysfunction in Alzheimer's disease: an hypothesis

Glutamate is a major excitatory neurotransmitter that has been implicated in memory formation and learning. This acidic amino acid also has neurotoxic properties, and in animals produces lesions reminiscent of human neurodegenerative diseases. Here we present evidence that supports the hypothesis that glutamate dysfunction is involved in the pathophysiology of Alzheimer's disease and can account for many of the neurochemical and behavioral deficits observed in this disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26817/1/0000375.pd

Evidence for a projection from the globus pallidus to the entopeduncular nucleus in the rat

Iontophoretic injections of the fluorescent retrograde tract tracer, Fluoro-gold, into the entopeduncular nucleus of the rat (homologous to the internal segment of the primate globus pallidus) resulted in a substantial number of retrogradely labeled neurons in the ipsilateral globus pallidus (homologous to the external segment of the primate globus pallidus). In experiments confirming this projection, iontophoretic injections of the anterograde tract tracer, Phaseolus vulgaris-leucoagglutinin, in the globus pallidus resulted in dense fiber and terminal labeling in the ipsilateral entopeduncular nucleus. This projection is topographically organized in rostral-caudal, medial-lateral and dorsal-ventral orientations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29229/1/0000284.pd

Muscarinic cholinergic receptors in human infant forebrain: [3H]Quinuclidinyl benzilate binding in homogenates and quantitative autoradiography in sections

The ontogeny of muscarinic receptors in human brain was studied by comparing [3H]quinuclidinyl benzilate ([3H]QNB) binding in postmortem tissue from infants 1 week to 3 months of age with binding in adult specimens. Saturation analysis with [3H]QNB and displacement studies with muscarinic antagonists and agonists in tissue homogenates demonstrated that binding sites in the infants' forebrain regions were present in adult or higher than adult concentrations (Bmax). Binding affinity (Kd) and pharmacological characteristics were nearly identical at the two ages. Quantitative receptor autoradiography demonstrated more [3H]QNB binding in the gray matter of infants than adults and revealed a marked difference between the two ages in the laminar distribution of binding sites in neocortex. In contrast to the adult pattern with higher binding in superficial layers 1-3 than in layers 4-6, the distribution in the immature cortex was inverted. These results suggest that muscarinic receptors in infants resemble closely those in mature brain. However, the topography of receptors in the immature neocortex is distinct and they are redistributed in a gradient from inside outward during postnatal development.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25719/1/0000276.pd

Loss of hippocampal [3H]TCP binding in Alzheimer's disease

We have previously demonstrated a marked loss in (NMDA) receptors in the hippocampus and cerebral cortex of patients dying with dementia of the Alzheimer type (DAT). In addition, we have found that the dissociative anesthetic N-(1-[2-thienyl]cyclohexyl)3,4-piperidine ([3H]TCP) binds to a site whose regional distribution is highly correlated with that of NMDA receptor sites. We studied the binding of [3H]TCP to sections of hippocampi from 8 controls, 12 patients with DAT and 7 patients with other dementias. [3H]TCP binding was significantly reduced in strata pyramidalia of CA1/CA2, CA3 and subiculum of DAT hippocampal formation compared to that of control. Labelled dissociative anestheties could potentially be used with positron emission tomography in the diagnosis of DAT.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26773/1/0000325.pd

In vivo [3H]flunitrazepam binding: imaging of receptor regulation

ABSTRACT ABBREVIATIONS: BDZ, benzodiazepine; GABA, 'y-aminobutyric acid; HO, Huntington's Disease; GP, globus pallidus; SNr, substantia nigra pars reticulata; FLU, flunitrazepam; PET, positron emission tomography; BBB, blood-brain barrier. 74