Learning and aging related changes in intrinsic neuronal excitability

Abstract

A goal of many laboratories that study aging is to find a key cellular change(s) that can be manipulated and restored to a young-like state, and thus, reverse the age-related cognitive deficits. We have chosen to focus our efforts on the alteration of intrinsic excitability (as reflected by the postburst afterhyperpolarization, AHP) during the learning process in hippocampal pyramidal neurons. We have consistently found that the postburst AHP is significantly reduced in hippocampal pyramidal neurons from young adults that have successfully learned a hippocampus-dependent task. In the context of aging, the baseline intrinsic excitability of hippocampal neurons is decreased and therefore cognitive learning is impaired. In aging animals that are able to learn, neuron changes in excitability similar to those seen in young neurons during learning occur. Our challenge, then, is to understand how and why excitability changes occur in neurons from aging brains and cause age-associated learning impairments. After understanding the changes, we should be able to formulate strategies for reversing them, thus making old neurons function more as they did when they were young. Such a reversal should rescue the age-related cognitive deficits.

Memory-enhancing intra-basolateral amygdala clenbuterol infusion reduces post-burst afterhyperpolarizations in hippocampal CA1 pyramidal neurons following inhibitory avoidance learning

“…After learning new tasks, CA1 pyramidal neurons exhibit transient reductions in AHPs (Farmer & Thompson, 2012;Moyer et al, 1996;Oh et al, 2010). Consistent with a hypothesis that AHP reductions serve as a cellular learning mechanism in hippocampal pyramidal neurons, drugs that reduce CA1 AHP amplitudes/durations improve acquisition in several different memory tasks (Disterhoft & Oh, 2006;Donzis & Thompson, 2014;Moyer, Thompson, Black, & Disterhoft, 1992).…”

“…Consistent with a hypothesis that AHP reductions serve as a cellular learning mechanism in hippocampal pyramidal neurons, drugs that reduce CA1 AHP amplitudes/durations improve acquisition in several different memory tasks (Disterhoft & Oh, 2006;Donzis & Thompson, 2014;Moyer, Thompson, Black, & Disterhoft, 1992). Normal aging, which is accompanied by enhanced AHPs (reduced excitability) in CA1 neurons, impairs learning (Disterhoft & Oh, 2006;Moyer et al, 1992;Oh et al, 2010). After acquisition of new spatial (Disterhoft & Oh, 2006;Oh et al, 2003) or trace eyeblink Thompson et al, 1996) learning tasks, reductions in the amplitude and area or duration of AHPs are seen in CA1 pyramidal neurons prepared in vitro up to 72 h post-learning.…”

“…AHP reductions are observed 1-24 h after IA learning in CA1 and CA3 pyramidal neurons (Farmer & Thompson, 2012). AHPs can be further segregated into fast (generated by BK channels), medium (generated by apamin-sensitive SK channels), and slow (generated by apamin-insensitive, currently unknown channels) AHPs (Farmer & Thompson, 2012;Oh et al, 2010;Sah & Faber, 2002). Time-course analyses of AHPs show fast (peak), medium (mAHP) and slow (sAHP) AHPs are all transiently reduced after learning an IA task with a highintensity footshock used as an aversive stimulus (Farmer & Thompson, 2012).…”

“…intrinsic excitability was enhanced (Farmer & Thompson, 2012), while immediate post-trial BLA lidocaine infusions blocked this learning-dependent plasticity in CA1 AHPs. Learning-dependent reductions in CA1 neuron AHPs are a reliable and highly replicable cellular mechanism expressed in hippocampus, with a time-course appropriate to support memory consolidation (Disterhoft & Oh, 2006;Farmer & Thompson, 2012;McKay, Mathews, Oliveira, & Disterhoft, 2009;Oh, Kuo, Wu, Sametsky, & Disterhoft, 2003;Oh, Oliveira, & Disterhoft, 2010;.…”

The L-type calcium channel Cav1.3 is required for proper hippocampal neurogenesis and cognitive functions

“…Cav1.2 knockout animals display deficits in spatial learning in the Morris water maze [8]. Cav1.2 dependent changes in cognition are primarily related to changes in LTP [8], whereas the low-voltage activated Cav1.3 channels apparently function as modulators of neuronal spiking behavior [23,24].…”