SELECTIVE MODULATION OF GABA(A) RECEPTORS BY ALUMINUM

Aluminum has been implicated in several neurodegenerative conditions i ncluding Alzheimer's disease. Because the mammalian olfactory system h as an unusual capacity for the uptake and transneuronal spread of inha led substances such as aluminum, whole cell recording techniques were used to examine the actions of aluminum on basic membrane properties a nd amino acid receptors on rat olfactory bulb mitral/tufted (M/T) neur ons in culture. Aluminum had little direct effects on M/T neurons. Alu minum (100 mu M) did not evoke a membrane current or alter action-pote ntial shape or duration. Aluminum also had no marked effects on the fa mily of voltage-gated membrane currents evoked by a series of 10-mV, 5 0-ms depolarizing steps. However, aluminum dramatically potentiated th e current evoked by 30 mu M gamma-aminobutyric acid (GABA) at concentr ations <100 mu M. Conversely, higher concentrations of aluminum blocke d the GABA-evoked current. The effects of aluminum on GABA-evoked curr ents were not voltage dependent. Aluminum (100 mu M) equally potentiat ed both inward currents at -30 mV and outward currents at + 30 mV. At 300 mu M, aluminum blocked both inward and outward currents to a simil ar extent. In some neurons, aluminum only blocked the current and pote ntiation was not observed. The biphasic action of aluminum on GABA-evo ked currents suggests separate binding sites: a high-affinity potentia ting site and a low-affinity inhibiting site. Despite its effects on G ABA-evoked currents, aluminum did not alter membrane currents evoked b y glutamate, N-methyl-D-aspartate, kainate, or glycine. Aluminum also did not reduce spontaneous excitatory synaptic activity, suggesting li ttle, if any, effect on glutamate release. Although a causal role for aluminum in Alzheimer's disease and other neuropathological conditions remains controversial, it is clear that elevated aluminum concentrati ons in the brain are associated with a variety of cognitive impairment s. The present results indicate that aluminum can alter the function o f GABA, receptors and may suggest that aluminum can contribute to cogn itive impairment through disruption of inhibitory circuits.