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The extracellular space (ECS) is the microenvironment of the nerve cells and an important communication channel, allowing for long-distance extrasynaptic communication between cells. Changes in ECS size, geometry, and composition have been reported in diverse (patho)physiological states, including aging. In the present study, real-time tetramethylammonium (TMA+) iontophoresis was used to quantify ECS diffusion parameters in different brain regions of adult and behaviorally characterized aged rats. Prior to ECS diffusion measurement, superior and inferior learners were selected from a large group of aged rats, according to their performance in the open-field water maze. The main finding was that the degree of impaired maze performance of old rats correlates, firstly, with decrease in ECS volume, loss of diffusion anisotropy in hippocampus, and degree of astrogliosis, and secondly, with disorganization of the astrocytic processes and reduction of hippocampal ECS matrix molecules. Importantly, no significant differences were found in the density of neurons in any region of the hippocampus or dentate gyrus. The alterations in hippocampal diffusion parameters evident in aged animals with severe learning deficits could account for the learning impairment, due to their effects on extrasynaptic volume transmission and/or on the "cross-talk" between synapses, which has been suggested to be involved in neural processes associated with learning and memory formation.

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ABSTRACT:Using quantitative receptor autoradiography, we assessed binding site densities and distribution patterns of glutamate, GABA A , acetylcholine (ACh), and monoamine receptors in the hippocampus of 32-month-old Fischer 344/Brown Norway rats. Prior to autoradiography, the rats were divided into two groups according to their retention performance in a water maze reference memory task, which was assessed 1 week after 8 days of daily maze training. The animals of the inferior group showed less long-term retention of the hidden-platform task but did not differ from superior rats in their navigation performance during place training and cued trials. The decreased retention performance in the group of inferior learners was primarily accompanied by increased a 1 -adrenoceptors in all hippocampal subregions under inspection (CA1-CA4 and dentate gyrus), while elevated a 2 -adrenoceptor binding was observed in the CA1 region and DG. Furthermore, inferior learners had higher NMDA binding in the CA2 and CA4 and increased 5-HT 1A binding sites in the CA2, CA3, and CA4 region. No significant differences between inferior and superior learners were evident with regard to AMPA, kainate, GABA A , muscarinergic M 1 , dopamine D 1 , and 5-HT 2 binding densities in any hippocampal region analyzed. These results show that increased NMDA, 5-HT 1A , and a-adrenoceptor binding in the hippocampus is associated with a decline in spatial memory. The increased receptor binding observed in the group of old rats with inferior maze performance might be the result of neural adaptation triggered by age-related changes in synaptic connectivity and/or synaptic activity. V V C 2006 Wiley-Liss, Inc.