Ca2+ Sources of sIAHP &Excitability Changes in Learning

  • Wu, Wendy, (PI)

Project: Research project

Description

Previously our laboratory has shown a reduction in the AHP and accommodation, i.e., an increase in neuronal excitability, in young and aging animals trained in hippocampally-dependent trace eyeblink conditioning. Because the reduction of the AHP and accommodation after training occurs in a time-limited fashion, we propose that these changes play a critical role during acquisition and initial consolidation processes of associative learning. Our preliminary data show a correlation between the amplitude of the AHP and the sI(AHP), a component of the AHP. Thus, we believe that the sI(AHP) is the current altered in learning. This proposal is designed to examine the cellular mechanisms that could underlie changes in the sI(AHP) in learning. The sI(AHP) is a calcium (Ca2+)-dependent current that is activated by a rise in the level of cytosolic Ca2+. In CA1 neurons, cytosolic Ca2+ is derived from both external and internal Ca2+ sources. External Ca2+ can enter the cell via channels and receptors, and internal Ca2+ can be released from internal stores in a process known as calcium-induced calcium release (CICR). The sI(AHP) is also modulated by various neurotransmitters and neuropeptides. Thus, the amplitude of the sI(AHP) depends on 3 factors: 1) the amount of Ca2+ influx, 2) the amount of Ca2+ release, and 3) modulation of the channels that underlie the sI(AHP) by various regulatory components or at the level of gene expression. To further explore the cellular mechanisms underlying changes of the SI(AHP), in learning, I have designed this research proposal to study the roles of external and internal Ca2+ sources to the generation of the sI(AHP) in the context of learning. The specific aims for this proposal are: Aim 1. Examining the role of internal Ca2+ in the generation of the sI(AHP). Previous experiments have shown the involvement of internal Ca2+-release channels in learning a hippocampally-dependent task, suggesting that CICR plays a role in learning, and further suggest that changes in CICR could lead to the learning-related reduction in the sI(AHP). In this study, CICR will be blocked with antagonists to examine the role of internal Ca2+ in the generation of the sI(AHP). Aim 2. Examining the role of external Ca2+ in the generation of the sI(AHP). Previous studies have shown a negative correlation between the density of the L-type Ca2+ channels (and therefore the L-type Ca2+ current) and Morris water maze performance, supporting a role for external Ca2+ source in learning. Ca2+ influx will be blocked with antagonists to examine the contribution of external Ca2+ toward the generation of the sI(AHP). Aim 3. Examining the relative contribution of each VGCC and its associated CICR in the generation of the sI(AHP). If there is a learning- related change in Ca2+ influx, then I will assay the relative contribution of each external Ca2+ source, i.e., each VGCC, to the generation of the sI(AHP) to determine which Ca2+ influx is altered in learning. Additionally, I will determine whether or not CICR triggered by each individual VGCC is altered in learning.
StatusActive
Effective start/end date9/29/01 → …

Funding

  • National Institutes of Health: $27,599.00
  • National Institutes of Health: $23,881.00
  • National Institutes of Health: $25,787.00

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Learning
Calcium
Neuropeptides
Neurotransmitter Agents
Research Design
Gene Expression
Neurons
Water

ASJC

  • Medicine(all)