Gene-targeted mice lacking the L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunit GluR-A exhibited normal development, life expectancy, and fine structure of neuronal dendrites and synapses. In hippocampal CA1 pyramidal neurons, GluR-A-/- mice showed a reduction in functional AMPA receptors, with the remaining receptors preferentially targeted to synapses. Thus, the CA1 soma-patch currents were strongly reduced, but glutamatergic synaptic currents were unaltered; and evoked dendritic and spinous Ca2+ transients, Ca2+-dependent gene activation, and hippocampal field potentials were as in the wild type. In adult GluR-A-/- mice, associative long-term potentiation (LTP) was absent in CA3 to CA1 synapses, but spatial learning in the water maze was not impaired. The results suggest that CA1 hippocampal LTP is controlled by the number or subunit composition of AMPA receptors and show a dichotomy between LTP in CA1 and acquisition of spatial memory.

We have determined the volume and location of hippocampal tissue required for normal acquisition of a spatial memory task Ibotenic acid was used to make bilateral symmetric lesions of 20-100% of hippocampal volume. Even a small transverse block (minislab) of the hippocampus (down to 26% of the total) could support spatial learning in a water maze, provided it was at the septal (dorsal) pole of the hippocampus. Lesions Lesions of the hippocampus disrupt learning and retention of spatial maze tasks (1-5). Recordings from pyramidal (6-9) and granule (9, 10) cells demonstrate firing in relation to the spatial position of the animal (place cells), even after relevant spatial cues are removed from the visual field (8,11,12 (>4 h apart). A transfer test, in which the rats swam for 60 s in the absence of the platform, was conducted at the start of days 5 and 7 (before sessions 9 and 13). Time spent swimming in the four quadrants was recorded. Finally, the rats were trained to escape onto a visible platform (three sessions). Curtains were drawn around the pool, and the platform position was varied from trial to trial. Evaluation of Lesions. After i.p. injections of Euthatal (sodium pentobarbital at 200 mg/kg), the rats were perfused intracardially with physiological saline and buffered 4% (vol/ vol) formaldehyde, and the brains were removed and stored in formaldehyde for >1 week. Frozen sections (30 pkm) were cut coronally and stained with thionin. Outlines of the lesions were traced onto 12 coronal line drawings of the hippocampus (19), spaced at 0.5-mm intervals from 1.8 to 7.3 mm posterior to bregma, which allowed determination of the volume of intact hippocampus between each pair of adjacent parallel surfaces. On seven brains with variously sized dorsal or ventral lesions, outlines and estimation of total volume were made by two experimenters (interobserver reliability r = 0.997; differences in volume estimates <3%). Rats with intended complete lesions were excluded if <80% of the hippocampus was damaged.Acetylcholinesterase (AChE). Sections from brains with unilateral dorsal (n = 2) or unilateral ventral (n = 2) hippocampal lesions, medial septal lesions (n = 2), or no lesion (n = 2) were stained for AChE 4 days after the lesion, as described (20).Field Potentials. Rats with ibotenic acid lesions of the ventral or dorsal two-thirds of the hippocampus were anesthetized i.p. with urethane (1.5 g/kg) or tribromoethanol Abbreviation: AChE, acetylcholinesterase. §To whom reprint requests should be sent at the t address. 9697The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

The hippocampus plays an essential role in spatial learning. To investigate whether the whole structure is equally important, we compared the effects of variously sized and localized hippocampal aspiration lesions on spatial learning in a Morris water maze. The volume of all hippocampal lesions was determined. Dorsal hippocampal lesions consistently impaired spatial learning more than equally large ventral lesions. The dorsal lesions had to be larger than 20% of the total hippocampal volume to prolong final escape latencies. The acquisition rate and precision on a probe test without platform were sensitive to even smaller dorsal lesions. The degree of impairment correlated with the lesion volume. In contrast, the lesions of the ventral half of the hippocampus spared both the rate and the precision of learning unless nearly all of the ventral half was removed. There was no significant effect of the location (dorsal or ventral) of damage to the overlying neocortex only. In conclusion, the dorsal half of the hippocampus appears more important for spatial learning than the ventral half. The spatial learning ability seems related to the amount of damaged dorsal hippocampal tissue, with a threshold at about 20% of the total hippocampal volume, under which normal learning can occur.

The search for cellular correlates of learning is a major challenge in neurobiology. The hippocampal formation is important for learning spatial relations. A possible long-lasting consequence ofsuch spatial learning is alteration of the size, shape, or number ofexcitatory synapses. The dendritic spine density is a good index for the number of hippocampal excitatory synapses. By using laser-scanning confocal microscopy, we observed a significantly increased spine density in CAl basal dendrites of spatially trained rats when compared to nontrained controls. With unchanged dendritic length, the higher spine density reflects an increased number of excitatory synapses per neuron associated with spatial learning.The hippocampal formation is closely related to spatial learning. This conclusion is based upon the presence of cells signaling the position of the animal in space and the interference with the ability to learn a spatial environment following mechanical or chemical inactivation of the hippocampus and neighboring cortex (1-4). Many of the hippocampal synapses have plastic properties, which may play a role in the learning process (5-7). Since learning effects are long-lasting, structural changes of hippocampal synapses are possible correlates to spatial learning. Among possible changes, the alteration of the size, shape, or number of excitatory synapses is among the most likely ones. Because virtually all excitatory synapses on hippocampal pyramidal cells contact dendritic spines (8), the number and distribution of these structures may be taken as an index of synaptic changes. Training in a complex environment causes spatial learning (9)(10)(11)(12). Whereas exposure to an enriched environment gives various structural changes in the visual cortex, there are few reports on such effects in the hippocampus (13). Using two-dimensional electron microscopy, Altschuler (14) found an increased number of synapses on CA3 cells in young rats after training in an enriched environment. In the absence of information on dendritic length, which is environmentally modifiable (15) On this background, we chose a hippocampus-dependent task. We tested whether or not spatial training of rats can give changes in dendritic spine density in the CAl field of the hippocampus. To avoid interference with developmental processes, we used adult animals.MATERIALS AND METHODS Environment. Adult male rats (250-460 g) were kept together in a large (2.5 x 2.0 x 1.7 m) cage with up to five floors mounted at various positions and connected with narrow ladders (Fig. 1A). Items expected to generate exploration (wooden blocks, freshly cut wood chips, branches, fresh leaves, plastic containers, paper bags) were distributed on the floors. Water and food bowls were hidden. All floors, ladders, and the position of water and food were changed between sessions. The rats were exposed to this environment for 4 hr/day for 18 days (behavioral study, n = 7) or 14-30 days (morphological study, n = 13). Between the exposures, the rats were housed in groups...

In an attempt to approach a system of isolated exercising muscle in humans, a model has been developed that enables the study of muscle activity and metabolism over the quadriceps femoris (QF) muscles while the rest of the body remains relaxed. The simplest version includes the subject sitting on a table with a rod connecting the ankle and the pedal arm of a bicycle ergometer placed behind the subject. Exercise is performed by knee extension from a knee angle of 90 to approximately 170 degrees while flywheel momentum repositions the relaxed leg during flexion. Experiments where electromyographic recordings have been taken from biceps femoris, gastrocnemius, tibialis anterior, and other muscles in addition to QF indicate that only the QF is active and that there is an equal activation of the lateral, medial, and rectus femoris heads relative to maximum. Furthermore, virtually identical pulmonary O2 uptake (Vo2) during and without application of a pressure cuff below the knee emphasizes the inactivity of the lower leg muscles. The advantages of the model are that all external work can be localized to a single muscle group suitable for taking biopsies and that the blood flow in and sampling from the femoral vein are representative of the active muscles. Thus all measurements can be closely related to changes in the working muscle. Using this model we find that a linear relationship exists between external work and pulmonary Vo2 over the submaximal range and the maximal Vo2 per kilogram of muscle may be as much as twice as high as previously estimated.