The Slow Afterhyperpolarization in Hippocampal CA1 Neurons Covaries with Spatial Learning Ability in Aged Fisher 344 Rats

Abstract

Rodents commonly exhibit age-related impairments in spatial learning tasks, deficits widely thought to reflect cellular or synaptic dysfunction in the hippocampus. Using whole-cell recordings, we examined the afterhyperpolarization (AHP) in CA1 pyramidal cells in hippocampal slices from young (4 -6 months of age) and aged (24 -26 months of age) Fisher 344 male rats that had been behaviorally characterized in the Morris water maze. The slow AHP (sAHP) recorded from learning-impaired aged rats (AI) was significantly larger than that seen in either age-matched unimpaired rats or young controls. Among aged rats, sAHP amplitude was inversely correlated with both acquisition and probe performance in the water maze. Action potential parameters among the three groups were similar, except for spike accommodation, which was more pronounced in the AI group. Intracellular application of the cAMP analog 8-CPT-cAMP suppressed the sAHP but failed to reveal any age-or performance-related differences in the medium AHP. 8-CPT-cAMP abolished the age-related difference in spike accommodation, whereas instantaneous firing frequency was unchanged. Calcium spikes were of similar amplitude in all three groups but were broader and had significantly larger tails in aged rats; these age-related changes could be mimicked in young neurons after exposure to BayK8644. The calcium spike among aged rats correlated with task acquisition in the maze but, unlike the sAHP, failed to correlate with probe performance. This is the first demonstration that sAHP amplitude covaries with spatial learning ability in aged rats, implying that CA1 excitability strongly influences certain aspects of cognitive function. Our findings also indicate that multiple processes, in addition to elevated calcium influx, conspire to induce cognitive decline during aging.

Individual differences in neurocognitive aging of the medial temporal lobe

“…Much of this evidence comes from in vitro preparations in which the synaptic functions/plasticity of the CA1 are isolated. That work has demonstrated significant changes in the excitability of neuron response to input in the form of an augmented after-hyperpolization (AHP) and a reduction in plasticity, using submaximal stimulation protocols, changes that have also been shown to correlate with cognitive outcome in aging (e.g., Tombaugh et al 2002Tombaugh et al , 2005. Our studies have similarly provided evidence for alterations affecting the function of connections in CA1.…”

Hippocampal Expression Analyses Reveal Selective Association of Immediate-Early, Neuroenergetic, and Myelinogenic Pathways with Cognitive Impairment in Aged Rats

“…Aged animals in the behaviorally characterized groups were separated into two categories, aged cognitively impaired (AI) and aged cognitively unimpaired (AU) based on their relative performance in the Morris water maze task as described previously (Tombaugh et al, 2005). Briefly, the maze consisted of a 1.6-mdiameter circular pool filled to within 15 cm of the rim with water (22°C) made opaque by the addition of nontoxic white latex paint (Createx Colors, East Granby, CT).…”

“…Aged learning-impaired rats were compared with aged unimpaired (and young) rats, a strategy that enhances power and reduces confounding effects of general aging (Markowska et al, 1989;Olton et al, 1991;Gallagher et al, 2003;Rowe et al, 2003). We chose the Morris water maze task to screen the aged animals because (1) it represents a (dorsal) hippocampal-dependent task (Moser and Moser, 1998) and (2) we and others have consistently found that there is considerable individual variability on this task, with some aged animals demonstrating the same proficiency as young animals and others exhibiting severe learning deficits (Yau et al, 2002;Gallagher et al, 2003;Rowe et al, 2003;Tombaugh et al, 2005). Together, the results provide an integrative overview of multiple novel and previously reported processes that selectively associate with aging-related cognitive impairment.…”

Enhanced Calcium Buffering in F344 Rat Cholinergic Basal Forebrain Neurons Is Associated With Age-Related Cognitive Impairment

“…Age-related increases in Ca 2ϩ currents, particularly the HVA L-type current (Campbell et al 1996;Moyer Jr and Disterhoft 1994;Thibault and Landfield 1996), have been implicated in age-related cognitive impairment (Disterhoft et al 1996;Tombaugh et al 2005). Increased HVA Ca 2ϩ channel function, in the form of reduced inactivation, has been described in BF neurons from aged rats (Murchison and Griffith 1996).…”