Aging-Related Hyperexcitability in CA3 Pyramidal Neurons Is Mediated by Enhanced A-Type K+ Channel Function and Expression.

Aging-related impairments in hippocampus-dependent cognition have been attributed to maladaptive changes in the functional properties of pyramidal neurons within the hippocampal subregions. Much evidence has come from work on CA1 pyramidal neurons, with CA3 pyramidal neurons receiving comparatively less attention despite its age-related hyperactivation being postulated to interfere with spatial processing in the hippocampal circuit. Here, we use whole-cell current-clamp to demonstrate that aged rat (29-32 months) CA3 pyramidal neurons fire significantly more action potentials (APs) during theta-burst frequency stimulation and that this is associated with faster AP repolarization (i.e., narrower AP half-widths and enlarged fast afterhyperpolarization). Using a combination of patch-clamp physiology, pharmacology, Western blot analyses, immunohistochemistry, and array tomography, we demonstrate that these faster AP kinetics are mediated by enhanced function and expression of Kv4.2/Kv4.3 A-type K(+) channels, particularly within the perisomatic compartment, of CA3 pyramidal neurons. Thus, our study indicates that inhibition of these A-type K(+) channels can restore the intrinsic excitability properties of aged CA3 pyramidal neurons to a young-like state. Significance statement: Age-related learning deficits have been attributed, in part, to altered hippocampal pyramidal neuronal function with normal aging. Much evidence has come from work on CA1 neurons, with CA3 neurons receiving comparatively less attention despite its age-related hyperactivation being postulated to interfere with spatial processing. Hence, we conducted a series of experiments to identify the cellular mechanisms that underlie the hyperexcitability reported in the CA3 region. Contrary to CA1 neurons, we demonstrate that postburst afterhyperpolarization is not altered with aging and that aged CA3 pyramidal neurons are able to fire significantly more action potentials and that this is associated with faster action potential repolarization through enhanced expression of Kv4.2/Kv4.3 A-type K(+) channels, particularly within the cell bodies of CA3 pyramidal neurons.

Robust hippocampal responsivity during retrieval of consolidated associative memory.

A contentious point in memory research is whether or not the hippocampus plays a time-limited role in the consolidation of declarative memories. A widely held view is that declarative memories are initially encoded in the hippocampus, then transferred to the neocortex for long-term storage. Alternate views argue instead that the hippocampus continues to play a role in remote memory recall. These competing theories are largely based on human amnesic and animal lesion/inactivation studies. However, in vivo electrophysiological evidence supporting these views is scarce. Given that other studies examining the role of the hippocampus in remote memory retrieval using lesion and imaging techniques in human and animal models have provided mixed results, it would be particularly useful to gain insight at the in vivo electrophysiological level. Here we report hippocampal single-neuron and theta activity recorded longitudinally during acquisition and remote retrieval of trace eyeblink conditioning. Results from conditioned rabbits were compared to those obtained from yoked pseudo-conditioned control rabbits. Results reveal continued learning-specific hippocampal activity one month after initial acquisition of the task. Our findings yield insight into the normal physiological responses of the hippocampus during memory processes and provide compelling in vivo electrophysiological evidence that the hippocampus is involved in both acquisition and retrieval of consolidated memories.

Functional reorganization of a prefrontal cortical network mediating consolidation of trace eyeblink conditioning.

The medial prefrontal cortex (mPFC) has been studied for its role in various cognitive functions, but the roles of its subregions remain unclear. We performed tetrode recordings simultaneously from prelimbic (PL) and rostral (rACC) and caudal (cACC) anterior cingulate subregions of the rabbit mPFC to understand their interactions during learning and tests of remote memory retention for whisker-signaled trace eyeblink conditioning. cACC neurons exhibited an innate response to the conditioning stimulus (CS) that rapidly decreased across sessions, suggesting an attentional role for facilitating CS-US associations. rACC neurons from conditioned rabbits exhibited robust responses to the CS that decreased within each session, possibly evaluating its emotional salience. PL neurons exhibited robust persistent activity during the trace interval during tests of remote memory retention, suggesting its involvement in retrieval and execution of a consolidated response. Mechanistically, conditioning was associated with a greater percentage of persistently responsive neurons than neurons from pseudoconditioned control rabbits, and responses differed significantly between trials with and without conditioned responses. Collectively, these responses reflect a functional reorganization of neural activity within the prefrontal network from an attentional mode to one that orchestrates the retrieval and execution of the learned response.

Ventral hippocampal neurons are shaped by experience to represent behaviorally relevant contexts.

Memories can be recalled at different levels of resolution, from a detailed rendition of specific events within a single experience to a broad generalization across multiple related experiences. Here we provide evidence that neural representations reflecting the specificity or generality of memories are differentially represented along the dorsoventral axis of the CA3 area of the rat hippocampus. In dorsal CA3, neurons rapidly associate the identity of events with specific locations whereas, in more ventrally located CA3 regions, neurons gradually accumulate information across extended training to form representations that generalize across related events within a spatial context and distinguish events across contexts.