Age-related biophysical alterations of hippocampal pyramidal neurons: implications for learning and memory

doi:10.1016/S1568-1637(01)00009-5

Ageing Research Reviews

Volume 1, Issue 2, April 2002, Pages 181-207

https://doi.org/10.1016/S1568-1637(01)00009-5 Get rights and content

Abstract

Normal brain aging is associated with deficits in learning and memory. The hippocampus, a structure critical for proper learning and memory functions, is frequently implicated in aging-related learning deficits. There are many reports of learning-related changes in hippocampal pyramidal neurons from animals that were trained in hippocampus-dependent learning paradigms. One consistent finding in hippocampal pyramidal neurons is a learning-related increase in postsynaptic neuronal excitability, resulting from a reduction in the postburst afterhyperpolarization (AHP). The hippocampus, as well as the ability to acquire hippocampus-dependent tasks, is particularly affected by aging. Correspondingly, hippocampal neurons also display an age-related decrease in excitability, resulting from an enhanced AHP. The correlation between neuronal excitability and learning ability strongly suggests that changes in the AHP are critically involved in learning and age-related learning deficits. Additional support for this argument comes from in vitro studies that examined the effect of compounds that facilitated learning in aging animals on the properties of CA1 pyramidal neurons. Many of these compounds increased the excitability of CA1 pyramidal neurons by reducing the AHP. Subsequent voltage-clamp recordings showed that AHP reduction by these compounds mainly reflects the reduction of two of its currents, the I_AHP and the sI_AHP. Conversely, age-related AHP enhancements primarily impact the I_AHP and the sI_AHP. Given that the I_AHP accounts for a small portion of the total AHP, and that the sI_AHP is the AHP current that most critically modulates neuronal excitability, changes in neuronal excitability seen in learning and in aging are predominantly caused by changes in the sI_AHP. The fact that the sI_AHP receives neuromodulation from many transmitter systems important for learning and sensitive to aging lends further support for its role in age-related learning deficits. In this article, we review: (1) two hippocampus-dependent learning tasks, trace eyeblink conditioning and Morris water maze training, that are used extensively in our laboratory to examine learning and aging-related learning deficits; (2) aging-related changes in several important neurotransmitter systems, and how the these changes impact learning and memory functions during aging; and (3) changes in the AHP and the sI_AHP in hippocampal pyramidal neurons in relation to compromised neurotransmission, as well as to learning, in aging animals. The correlations between a reduction in the sI_AHP in learning, and an enhancement in the sI_AHP in aging provide compelling evidence that this current plays a critical role in cognitive functions, and further suggest that the key modulators of the AHP are good candidates for future therapeutic interventions in age-related neurodegenerative diseases.

Introduction

The hippocampus is critically involved in learning and memory (Cohen and Eichenbaum, 1993). Hippocampal lesions in humans and animals cause severe deficits in the ability to transfer information from short-term to long-term stores, thus preventing the formation of new memories (Squire, 1987). The hippocampus, as well as learning and memory processes that depend on proper hippocampal function, is particularly vulnerable to the aging process (Jack et al., 2000, Petersen et al., 2000). Aging animals and humans have shown an impairment in acquiring hippocampus-dependent learning tasks while they are not impaired in versions of the same task that does not require the hippocampus (Thompson et al., 1996a, Knuttinen et al., 2001a, Knuttinen et al., 2001b).

Section snippets

Hipocampus-dependent tasks

Our laboratory routinely uses two hippocampus-dependent tasks, trace eyeblink conditioning (Solomon et al., 1986, Moyer et al., 1990, Weiss et al., 1999b) and Morris water maze learning (Morris, 1981, Morris et al., 1982), to assess the contribution of the hippocampus to learning. Successful acquisition of these tasks requires a properly functioning and intact hippocampus (Solomon et al., 1986, Moyer et al., 1990, Weiss et al., 1999a, McGlinchey-Berroth et al., 1997, Clark and Squire, 1998,

Postsynaptic excitability increases in learning

An increase in postsynaptic excitability is a form of learning-induced plasticity. In hippocampal pyramidal neurons, action potentials are followed by a postburst afterhyperpolarization (AHP), which serves to limit further firing in response to a sustained excitation in a process known as spike frequency adaptation (accommodation). Thus, measurement of the AHP serves as an indicator for neuronal excitability. Our laboratory has shown that in rabbit CA1 and CA3 hippocampal pyramidal neurons, the

Components of the AHP altered in learning

Based on kinetic and pharmacological criteria, the AHP can be separated into fast, medium, and slow components (fAHP, mAHP, sAHP, respectively; for reviews, Storm, 1990, Sah, 1996). The currents underlying these components are four classes of outward K⁺ currents (I_C, I_M, I_AHP, and sI_AHP) and a mixed cationic current, I_Q/I_h (Halliwell and Adams, 1982, Lancaster and Adams, 1986, Storm, 1990, Sah, 1996, Maccaferri et al., 1993, Alger et al., 1994, Oh et al., 2000a, Stocker et al., 1999). Three of

Cellular mechanisms underlying learning-related reduction in the AHP

Protein kinase C gamma (PKCγ) is a Ca²⁺-activated, phospholipid-sensitive protein kinase that modulates the AHP (Malenka et al., 1986, Agopyan and Agopyan, 1991). Our laboratory and others have demonstrated an increase in the PKCγ-immunoreactivity in CA1 pyramidal cells of rats, mice, and rabbits after learning hippocampus-dependent spatial and associative tasks (for reviews, Van der Zee et al., 1997a, Van der Zee et al., 1997b). The increase in PKCγ-immunoreactivity is learning-specific,

Postsynaptic excitability decreases in aging: implications for age-related learning deficits

Acquisition of the trace eyeblink conditioning response is impaired in aging rats and rabbits (Knuttinen et al., 2001a, Thompson et al., 1996b, Weiss et al., 2000). Interestingly, the AHP and accommodation are enhanced in CA1 neurons of rabbits and rats at ages that show learning deficits (Fig. 3; Landfield and Pitler, 1984, Moyer et al., 1992, Moyer et al., 2000, Oh et al., 1999b). Although many aging animals failed to acquire the trace eyeblink conditioned response (Thompson et al., 1996a,

Mechanisms underlying aging-related enhancement in the sI_AHP

The currents underlying the AHP are modulated by a variety of neurotransmitters, neuromodulators, and neuropeptides (for review, see Storm, 1990). For example, I_M is reduced by acetylcholine (for review, Storm, 1989, Cole and Nicoll, 1984, Dutar and Nicoll, 1989) and enhanced by somatostatin (Schweitzer et al., 1990). The I_AHP and the sI_AHP are reduced by metabotropic glutamate agonists (Liu et al., 1993), acetylcholine (Madison et al., 1987), serotonin (Colino and Halliwell, 1987), histamine (

‘Cholinergic hypothesis’ of cognitive aging

One hypothesis for the neurobiological basis of cognitive aging focuses on the basal forebrain cholinergic system (Bartus et al., 1982). Atrophy and degeneration of cholinergic neurons are detected in aged brains (Fischer et al., 1992, Smith and Booze, 1995, Stroessner-Johnson et al., 1992), and marked pathology affects this system in Alzheimer's disease (Coyle et al., 1983, Davies and Maloney, 1976). As I_M, I_AHP, and the sI_AHP are all reduced by acetylcholine, a reduction in cholinergic input

Glutamatergic neurotransmission in aging

Glutamate is the neurotransmitter for most of the excitatory synapses in the mammalian central nervous system. Glutamate receptors are divided into two distinct groups, ionotropic and metabotropic receptors (mGluRs) (for review, see Ozawa et al., 1998). Both ionotropic receptors and mGluRs have been implicated in learning and in aging.

N-methyl-d-aspartate (NMDA) receptors are a class of ionotropic receptors. Previous studies have shown an age-related decline in NMDA receptor density, as well as

Monoaminergic systems in aging

In addition to the loss of cholinergic neurons in the basal forebrain and altered glutamatergic transmission, aging also affects dopaminergic, noradrenergic and serotonergic processes. All of these systems have been implicated to interact with cholinergic system in learning. Many behavioral studies suggest that the serotonergic system interacts with the cholinergic system in learning (for review, Richter-Levin and Segal, 1996). For example, behavioral deficits produced by cholinergic lesions

‘Ca²⁺ hypothesis of aging’

Many studies have revealed an altered Ca²⁺ homeostasis in aging (Khachaturian, 1989, Disterhoft et al., 1994, Thibault et al., 1998, Verkhratsky and Toescu, 1998). Our laboratory and others have demonstrated that in aging neurons, Ca²⁺ action potentials are larger and have a longer plateau phase than in young neurons (Pitler and Landfield, 1990, Moyer and Disterhoft, 1994). This increase in Ca²⁺ influx (Landfield and Pitler, 1984) is at least partially caused by an increase in the functional

Effects of neuromodulation on the sI_AHP in hippocampal pyramidal neurons

Changes in the sI_AHP in learning and in aging undoubtedly reflect changes in the degree of neuromodulation for this current. Although the effects of these transmitters on the sI_AHP and subsequent neuronal excitability have been examined in vitro, to what extent each system contributes to modify the sI_AHP during learning and aging processes is hard to decipher. In pyramidal neurons, the sI_AHP is maintained by a balance between the activities of protein kinases and phosphatases under basal

Functional significance of learning-related AHP reductions: implications from in vivo recordings

We have identified learning- and aging-related changes in the properties of CA1 pyramidal neurons recorded in slice preparations. However, the critical afferent and efferent connections of these neurons are severed during the preparation of brain slices. To understand the functional significance of altered properties of hippocampal neurons in learning and in aging, we performed a series of in vivo studies to examine activity changes in CA1 pyramidal neurons during the acquisition and

Conclusion

The hippocampus is important for learning various associative tasks assayed by behavioral studies. Cognitive deficits related to aging involve concomitant alterations of various neurochemical systems in several brain regions including the hippocampus. These alterations occur in a complex way that involves a loss of cholinergic neurons, changes in Ca²⁺ dynamics in aging cells, and dysfunctions of the dopaminergic, noradrenergic, serotonergic, and glutamatergic systems. How these systems interact

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ReviewAge-related biophysical alterations of hippocampal pyramidal neurons: implications for learning and memory

Abstract

Introduction

Section snippets

Hipocampus-dependent tasks

Postsynaptic excitability increases in learning

Components of the AHP altered in learning

Cellular mechanisms underlying learning-related reduction in the AHP

Postsynaptic excitability decreases in aging: implications for age-related learning deficits

Mechanisms underlying aging-related enhancement in the sIAHP

‘Cholinergic hypothesis’ of cognitive aging

Glutamatergic neurotransmission in aging

Monoaminergic systems in aging

‘Ca2+ hypothesis of aging’

Effects of neuromodulation on the sIAHP in hippocampal pyramidal neurons

Functional significance of learning-related AHP reductions: implications from in vivo recordings

Conclusion

Mech. Ageing Dev.

Neurobiol. Aging

Neuron

Brain Res.

Lancet

Brain Res.

Brain Res.

Life Sci.

Life Sci.

Neurobiol. Aging

Behav. Neural Biol.

Eur. J. Pharmacol.

Brain Res. Brain Res. Rev.

Neurosci. Lett.

Neuroscience

Physiol. Behav.

Neurosci. Lett.

Neuroscience

Brain Res.

Prog. Brain Res.

Brain Res. Mol. Brain Res.

Neurosci. Lett.

Eur. J. Pharmacol.

Neurobiol. Aging

Pharmacol. Biochem. Behav.

Brain Res.

Mech. Ageing Dev.

Brain Res.

Neuropharmacology

Pharmacol. Biochem. Behav.

Learning Motivation

Neuron

Tyrosine kinase inhibitors enhance a Ca(2+)-activated K+ current (IAHP) and reduce IAHP suppression by a metabotropic glutamate receptor agonist in rat dentate granule neurones

J. Physiol.

Effects of protein kinase C activators and inhibitors on membrane properties, synaptic responses, and cholinergic actions in CA1 subfield of rat hippocampus in situ and in vitro

Synapse

Single-channel activity correlated with medium-duration, Ca-dependent K current in cultured rat hippocampal neurones

Neurosci. Lett.

Calcium-mediated reduction of ionic currents: a biophysical memory trace

Science

The cholinergic hypothesis of geriatric memory dysfunction

Science

Distribution of slow AHP channels on hippocampal CA1 pyramidal neurons

J. Neurophysiol.

Somatic colocalization of rat SK1 and D class (Cav 1.2) L-type calcium channels in rat CA1 hippocampal pyramidal neurons

J. Neurosci.

Aging changes in voltage-gated calcium currents in hippocampal CAI neurons

J. Neurosci.

Potassium conductances in hippocampal neurons blocked by excitatory amino-acid transmitters

Nature

Expression of alpha 1D subunit mRNA is correlated with L-type Ca2+ channel activity in single neurons of hippocampal ‘zipper’ slices

Proc. Natl. Acad. Sci. USA

Classical conditioning and brain systems: the role of awareness

Science

Memory, Amnesia, and the Hippocampal Syster

Long-lasting increase in cellular excitability associated with the priming of LTP induction in rat hippocampus

J. Neurophysiol.

Differential modulation of three separate K-conductances in hippocampal CA1 neurons by serotonin

Nature

Classical conditioning reduces amplitude and duration of calcium-dependent afterhyperpolarization in rabbit hippocampal pyramidal cells

J. Neurophysiol.

Alzheimer's disease: a disorder of cortical cholinergic innervation

Science

Review
Age-related biophysical alterations of hippocampal pyramidal neurons: implications for learning and memory

Mechanisms underlying aging-related enhancement in the sI_AHP

‘Ca²⁺ hypothesis of aging’

Effects of neuromodulation on the sI_AHP in hippocampal pyramidal neurons

Tyrosine kinase inhibitors enhance a Ca⁽²⁺⁾-activated K⁺ current (IAHP) and reduce IAHP suppression by a metabotropic glutamate receptor agonist in rat dentate granule neurones

Expression of alpha 1D subunit mRNA is correlated with L-type Ca²⁺ channel activity in single neurons of hippocampal ‘zipper’ slices