Showing papers by "Edson X. Albuquerque published in 2004"

The nicotinic acetylcholine receptor subtypes and their function in the hippocampus and cerebral cortex.

Abstract: Nicotinic acetylcholine receptors (nAChRs) are widely distributed in the central nervous system and have been implicated in multiple behavioral paradigms and pathological conditions. Nicotinic therapeutic interventions require an extensive characterization of native nAChRs including mapping of their distribution and function in different brain regions. Here, we describe the roles played by different nAChRs in affecting neuronal activity in the hippocampus and cerebral cortex. At least three distinct functional nAChR subtypes (alpha 7, alpha 4 beta 2, alpha 3 beta 4) can be detected in the hippocampal region, and in many instances a single neuron type is found to be influenced by all three nAChRs. Further, it became clear that GABAergic and glutamatergic inputs to the hippocampal interneurons are modulated via different subtypes of nAChRs. In the cerebral cortex, GABAergic inhibition to the layer V pyramidal neurons is enhanced predominantly via activation of alpha 4 beta 2 nAChR and to a minor extent via activation of alpha 7 nAChR. Such diversity offers pathways by which nicotinic drugs affect brain function.

Targeted Deletion of the Kynurenine Aminotransferase II Gene Reveals a Critical Role of Endogenous Kynurenic Acid in the Regulation of Synaptic Transmission via α7 Nicotinic Receptors in the Hippocampus

Abstract: It has been postulated that endogenous kynurenic acid (KYNA) modulates α7* nicotinic acetylcholine receptor (nAChR) and NMDA receptor activities in the brain.[a][1] To test this hypothesis, α7* nAChR and NMDA receptor functions were studied in mice with a targeted null mutation in the gene encoding kynurenine aminotransferase II ( mKat - 2 -/- mice), an enzyme responsible for brain KYNA synthesis. At 21 postnatal days, mKat - 2 -/- mice had lower hippocampal KYNA levels and higher spontaneous locomotor activity than wild-type (WT) mice. At this age, α7* nAChR activity induced by exogenous application of agonists to CA1 stratum radiatum interneurons was ∼65% higher in mKat - 2 -/- than WT mice. Binding studies indicated that the enhanced receptor activity may not have resulted from an increase in α7* nAChR number. In 21-d-old mKat - 2 -/- mice, endogenous α7* nAChR activity in the hippocampus was also increased, leading to an enhancement of GABAergic activity impinging onto CA1 pyramidal neurons that could be reduced significantly by acute exposure to KYNA (100 nM). The activities of GABAA and NMDA receptors in the interneurons and of α3β4* nAChRs regulating glutamate release onto these neurons were comparable between mKat - 2 -/- and WT mice. By 60 d of age, KYNA levels and GABAergic transmission in the hippocampus and locomotor activity were similar between mKat - 2 -/- and WT mice. Our findings that α7* nAChRs are major targets for KYNA in the brain may provide insights into the pathophysiology of schizophrenia and Alzheimer's disease, disorders in which brain KYNA levels are increased and α7* nAChR functions are impaired. [1]: #fn-1

Spine density and dendritic branching pattern of hippocampal CA1 pyramidal neurons in neonatal rats chronically exposed to the organophosphate paraoxon.

Abstract: The organophosphate cholinesterase (ChE) inhibitor paraoxon is the oxidized active metabolite of parathion, a pesticide whose use in agriculture has been matter of increasing concern. The present work was aimed at reproducing a prolonged exposure to low concentrations of paraoxon and assessing possible damage to the hippocampus during the period of most significant cholinergic development. Male Wistar rats were given, from P8 to P20, subcutaneous daily injections of paraoxon (0.1, 0.15 and 0.2mg/kg). The rate of body weight gain was reduced by all doses of paraoxon and brain ChE activity progressively decreased up to 60% by P21. Some deaths occurred in the beginning of the treatment, but the surviving animals showed neither convulsions nor overt signs of cholinergic hyperstimulation. Morphometric analysis of Lucifer Yellow-stained CA1 pyramidal neurons in coronal sections of the hippocampus showed that by P21 paraoxon caused a decrease in spine density on basal but not on secondary apical dendrites. The dendritic arborization and the pyramidal and granular cell body layers were not altered by paraoxon. ChE staining decreased in all hippocampal and dentate gyrus regions studied, whereas choline acetyltransferase (ChAT) and zinc-positive fibers remained as in control. In summary, chronic exposure to low paraoxon concentrations during the period of rapid brain development caused significant and selective decrease in basal dendritic spine density of the CA1 pyramidal neurons. Distinct modulation of the basal tree at the stratum oriens by the interplay of cholinergic afferent and GABAergic interneurons, as well as the remodeling process in response to a repetitive and rather mild paraoxon insult, may account for this selective susceptibility of basal dendritic spines. The hippocampal alterations described here occurred in the absence of toxic cholinergic signs and may affect brain development and cause functional deficits that could continue into adulthood.

Pb2+ via protein kinase C inhibits nicotinic cholinergic modulation of synaptic transmission in the hippocampus.

Abstract: The present study was designed to investigate the effects of Pb(2+) on modulation of synaptic transmission by nicotinic receptors (nAChRs) in the rat hippocampus. To this end, inhibitory and excitatory postsynaptic currents (IPSCs and EPSCs, respectively) were recorded by means of the whole-cell mode of the patch-clamp technique from rat hippocampal neurons in culture. Acetylcholine (ACh, 1 mM; 1-s pulses) triggered GABA release via activation of alpha4beta2* and alpha7* nAChRs. It also triggered glutamate release via activation of alpha7* nAChRs. Pb(2+) (0.1 and 1 microM) blocked ACh-triggered transmitter release. Blockade by Pb(2+) of ACh-triggered IPSCs was partially reversible upon washing of the neurons. In contrast, even after 30- to 60-min washing, there was no reversibility of Pb(2+)-induced blockade of ACh-triggered EPSCs. The effects of Pb(2+) on GABA release triggered by activation of alpha7* and alpha4beta2* nACRs were mimicked by the protein kinase C (PKC) activator phorbol-12-myristate-13-acetate (1 microM) and blocked by the indolocarbazole Go 7874 (50 nM) and the bisindolylmaleimide Ro-31-8425 (150 nM), which are selective PKC inhibitors. After washing of fully functional neuronal networks that had been exposed for 5 min to Pb(2+), the irreversible inhibition by Pb(2+) of ACh-triggered glutamate release was partially overridden by a disinhibitory mechanism that is likely to involve alpha4beta2* nAChR activation in interneurons that synapse onto other interneurons synapsing onto pyramidal neurons. Long-lasting inhibition of alpha7* nAChR modulation of synaptic transmission may contribute to the persistent cognitive impairment that results from childhood Pb(2+) intoxication.