G. Rao

Age-related decrease in the N-methyl-D-aspartateR-mediated excitatory postsynaptic potential in hippocampal region CA1.

Glutamatergic fast synaptic transmission is known to be altered with age in a region-specific manner in hippocampus of memory-impaired old rats. In the present experiment, presynaptic fiber potentials and non-N-methyl-D-aspartate (NMDAR) and NMDAR-mediated synaptic responses in CA1 were compared in three ages of behaviorally characterized male F-344 rats. In the CA1 region, old rats showed approximately equivalent reductions in non-NMDAR- and NMDAR-excitatory postsynaptic potential amplitudes for a given size of presynaptic fiber potential. There was no change in magnitude of the presynaptic response itself at any stimulus level. These results are consistent with the hypothesis that there is a reduction in the number of Schaffer collateral synapses per presynaptic axon. This pattern of results in CA1 is very different from what is known to occur at the perforant path-granule cell synapse. In fascia dentata the non-NMDAR-mediated excitatory postsynaptic potential is increased in amplitude, although the NMDAR-mediated excitatory postsynaptic potential is reduced for a given presynaptic input. These data suggest that age-related functional alterations in neurotransmitter receptor subtypes occur differentially between closely-related anatomical subregions.

Role of temporal summation in age-related long-term potentiation–induction deficits

Hippocampal long‐term potentiation (LTP) is reduced in aged relative to young F‐344 rats when peri‐threshold stimulation protocols (several stimulus pulses at 100–200 Hz) are used. The present study was designed to examine the possibility that this LTP‐induction deficit is caused by a reduced overlap of Schaffer‐collateral inputs onto CA1 pyramidal cells (input cooperativity). This reduced input cooperativity would decrease the levels of postsynaptic depolarization during LTP induction, which might account for the age‐related LTP deficit.

LTP induction threshold change in old rats at the perforant path–granule cell synapse ☆

Old, memory-deficient rats do not show a change in the threshold for long-term potentiation (LTP) induction in hippocampal region CA1. This observation suggests that defective NMDA receptor mechanisms at the Schaffer collateral-CA 1 pyramidal cell synapse cannot explain age-related LTP induction deficits that are observed under some stimulation protocols. The effects of aging on functional electrophysiology are not, however, identical between hippocampal subregions. In fact, at the perforant path-granule cell synapse of rats NMDA receptor-mediated responses are reduced, suggesting a possible change in the threshold for LTP induction at this synapse. This hypothesis was tested in the present experiment. We found that when weak orthodromic stimulation of medial perforant path fibers is paired with intracellular current injection of granule cells, the threshold for LTP induction is elevated in aged, spatial memory-impaired rats compared to middle-aged and young controls. Thus, in addition to there being fewer total medial perforant path synaptic contacts in old rats, greater depolarization and input convergence is required before durable modification of synaptic strength can be induced.

Increase in perforant path quantal size in aged F-344 rats

The data presented here confirm and extend the evidence for fewer, but stronger, perforant path synaptic connections onto the granule cells of the hippocampus in old F-344 rats. The old animals used in the present report were drawn from a population that showed deficits in the retention of a spatial problem in the Morris water task. Using the method of minimal-stimulation of perforant path afferents, unitary granule cell EPSPs were found to be larger in the 25-month than in the 6- and 9-month age groups. Furthermore, applying statistical methods for quantal analysis, data are presented that suggest that the larger synaptic responses of the old rats come about through an increase in quantal size. These experiments therefore suggest that individual synapses become more powerful in the perforant pathway of old rats, and that this strengthening occurs through an increase in quantal size. The implications of these findings for hippocampal information processing are discussed.

Specificity of functional changes during normal brain aging.

Although there is no question that age-related alterations in neural function occur in the central nervous system (CNS) of mammals, these changes tend to be somewhat circumscribed rather than completely global, even in pathological conditions. Examples of this kind of specificity of functional neural change are drawn from experiments on the electrophysiology of the senescent rat hippocampus.

Effects of age on L-glutamate-induced depolarization in three hippocampal subfields.

The effects of aging on the translation of L-glutamate-induced depolarization into hippocampal neuronal firing frequency were studied in vitro. L-glutamate was iontophoretically-applied to the somatic region of extracellularly recorded single units. In none of the three principal hippocampal subfields (fascia dentata, CA3, and CA1) were there any effects of age on neuronal sensitivity to L-glutamate. Because there are pronounced, region-specific age effects on AMPA sensitivity (3), these results are in agreement with the conclusions of other investigators that the depolarization caused by exogenously applied L-glutamate probably exerts its effects through nonsynaptic mechanisms. These mechanisms, however, which lead to powerful depolarization and action potentials in hippocampal cells, are unaffected by age.

The influence of postmortem delay on evoked hippocampal field potentials in the in vitro slice preparation

The influence of postmortem delay, and thus in situ anoxia/ischemia, on the recovery, viability, and maintenance of in vitro hippocampal slices was studied parametrically. Brains from rats were kept in situ for delays of 5, 30, 60, 90, 120, or 180 min before dissection and slicing of the tissue. Using standard in vitro conditions, Schaffer collateral and perforant path-evoked field potentials were recorded in the respective cell layers at 2, 4, and 8 h after beginning in vitro maintenance. With submaximal stimulus intensities the percentage of slices displaying at least a 1-mV population spike remained above 20% for all postmortem delays, and this measure of viability was indistinguishable (65%) across the delays of 5 and 30 min in both CA1 and fascia dentata (FD). The amplitudes of the EPSP and population spike and the population spike-to-EPSP ratio tended to decline with anoxic delay in both CA1 and FD; however, approximately half-maximal population spikes averaged greater than 3 mV, even for the longest postmortem delay of 3 h. These results indicate that the delay between death and preparation of in vitro hippocampal slices is less important for obtaining physiologically viable slices than previously believed. These data also imply that meaningful electrophysiological information about premortem brain conditions may be inferred from nervous system tissue which is not available immediately after death.