Biomedical subjects

M Matthew Oh

Publications and source records attributed to M Matthew Oh.

6 recordsLinked to original sources

PubMed2006

Learning, aging and intrinsic neuronal plasticity.

In vitro experiments indicate that intrinsic neuronal excitability, as evidenced by changes in the post-burst afterhyperpolarization (AHP) and spike-frequency accommodation, is altered during learning and normal aging in the brain. Here we review these studies, highlighting two consistent findings: (i) that AHP and accommodation are reduced in pyramidal neurons from animals that have learned a task; and (ii) that AHP and accommodation are enhanced in pyramidal neurons from aging subjects, a cellular change that might contribute to age-related learning impairments. Findings from in vivo single-neuron recording studies complement the in vitro data. From these consistently reproduced findings, we propose that the intrinsic AHP level might determine the degree of synaptic plasticity and learning. Furthermore, it seems that reductions in the AHP must occur before learning if young and aging subjects are to learn a task successfully.

Aging↗

PubMed2006

Pharmacological and molecular enhancement of learning in aging and Alzheimer's disease.

When animals learn hippocampus-dependent associative and spatial tasks such as trace eyeblink conditioning and the water maze, CA1 hippocampal neurons become more excitable as a result of reductions in the post-burst, slow afterhyperpolarization. The calcium-activated potassium current that mediates this afterhyperpolarization is activated by the calcium influx that occurs when a series of action potentials fire and serves as a modulator of neuronal firing frequency. As a result, spike frequency accommodation is also reduced after learning. Neuronal calcium buffering processes change and/or voltage-dependent calcium currents increase during aging; leading to enhancements in the slow afterhyperpolarization, increased spike frequency accommodation and age-associated impairments in learning. We describe a series of studies done to characterize this learning-specific enhancement in intrinsic neuronal excitability and its converse in aging brain. We have also combined behavioral pharmacology and biophysics in experiments demonstrating that compounds that increase neuronal excitability in CA1 pyramidal neurons also enhance learning rate of hippocampus-dependent tasks, especially in aging animals. The studies reviewed here include those using nimodipine, an L-type calcium current blocker that tends to cross the blood-brain barrier; metrifonate, a cholinesterase inhibitor; CI1017, a muscarinic cholinergic agonist; and galantamine, a combined cholinesterase inhibitor and nicotinic agonist. Since aging is the chief risk factor for Alzheimer's disease, a disease that targets the hippocampus and associated brain regions and markedly impairs hippocampus-dependent learning, these compounds have potential use as treatments for this disease. Galantamine has been approved by the USDA for this purpose. Finally, we have extended our studies to the TG2576 transgenic mouse model of Alzheimer's disease (AD), that overproduces amyloid precursor protein (APP) and increases levels of toxic beta-amyloid in the brain. Not only do these mice show deficits in hippocampus-dependent learning as they age, but their hippocampal neurons show a reduced capacity to increase their levels of intrinsic excitability with reductions in the slow afterhyperpolarization after application of the muscarinic agonist carbachol. These TG2576 APP overproducing mice were crossed with BACE1 knockout mice, that do not produce beta-amyloid because cleavage of APP by the beta-site APP cleaving enzyme 1 (BACE1) is a critical step in its formation. Not only was hippocampus-dependent learning rescued in the bigenic TG2576-BACE1 mice, but the capacity of hippocampal neurons to show normal enhancements of intrinsic excitability was restored. The series of studies reviewed here support our hypothesis that enhancement in intrinsic excitability by reductions in calcium-activated potassium currents in hippocampal neurons is an important cellular mechanism for hippocampus-dependent learning.

Aging↗

PubMed2003

Watermaze learning enhances excitability of CA1 pyramidal neurons.

The dorsal hippocampus is crucial for learning the hidden-platform location in the hippocampus-dependent, spatial watermaze task. We have previously demonstrated that the postburst afterhyperpolarization (AHP) of hippocampal pyramidal neurons is reduced after acquisition of the hippocampus-dependent, temporal trace eyeblink conditioning task. We report here that the AHP and one or more of its associated currents (IAHP and/or sIAHP) are reduced in dorsal hippocampal CA1 pyramidal neurons from rats that learned the watermaze task as compared with neurons from control rats. This reduction was a learning-induced phenomenon as the AHP of CA1 neurons from rats that failed to learn the hidden-platform location was similar to that of neurons from control rats. We propose that reduction of the AHP in pyramidal neurons in regions crucial for learning is a cellular mechanism of learning that is conserved across species and tasks.

Action Potentials↗

PubMed2003

Modulation of cholinergic transmission enhances excitability of hippocampal pyramidal neurons and ameliorates learning impairments in aging animals.

Four cholinesterase inhibitors have been approved by the US Food and Drug Administration for treating behavioral symptoms of Alzheimer's disease. Here we review our experiences with two cholinesterase inhibitors (metrifonate and galanthamine) and a muscarinic acetylcholine receptor agonist (CI-1017) in behavioral pharmacological and brain slice experiments in aging and young rabbits. Aging rabbits are impaired in their ability to acquire the hippocampus-dependent trace eyeblink conditioning task, as compared to young controls. A large proportion of aging animals cannot reach behavioral criterion in this task. Those that do learn, do so more slowly. In addition, the post-burst afterhyperpolarization and spike frequency accommodation is increased in hippocampal pyramidal neurons from aging animals, i.e., cellular excitability is reduced as compared to those from young animals. Metrifonate, galanthamine, and CI-1017 reduced the learning deficits observed in aging rabbits so that they learned almost as quickly as young controls. These cholinergic compounds also enhanced the postsynaptic excitability of hippocampal pyramidal neurons in vitro. Therefore, we propose that the amelioration of learning impairment with the cholinergic compounds may in part be due to the enhanced excitability of hippocampal pyramidal neurons. The potential relevance of our studies to further understanding the cellular and behavioral changes that occur with normal aging and Alzheimer's Disease is discussed.

Aging↗

PubMed2002

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

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.

Aging↗

PubMedDate not supplied

Galantamine facilitates acquisition of hippocampus-dependent trace eyeblink conditioning in aged rabbits.

Cholinergic systems are critical to the neural mechanisms mediating learning. Reduced nicotinic cholinergic receptor (nAChR) binding is a hallmark of normal aging. These reductions are markedly more severe in some dementias, such as Alzheimer's disease. Pharmacological central nervous system therapies are a means to ameliorate the cognitive deficits associated with normal aging and aging-related dementias. Trace eyeblink conditioning (EBC), a hippocampus- and forebrain-dependent learning paradigm, is impaired in both aged rabbits and aged humans, attributable in part to cholinergic dysfunction. In the present study, we examined the effects of galantamine (3 mg/kg), a cholinesterase inhibitor and nAChR allosteric potentiating ligand, on the acquisition of trace EBC in aged (30-33 months) and young (2-3 months) female rabbits. Trace EBC involves the association of a conditioned stimulus (CS) with an unconditioned stimulus (US), separated by a stimulus-free trace interval. Repeated CS-US pairings results in the development of the conditioned eyeblink response (CR) prior to US onset. Aged rabbits receiving daily injections of galantamine (Aged/Gal) exhibited significant improvements compared with age-matched controls in trials to eight CRs in 10 trial block criterion (P = 0.0402) as well as performance across 20 d of training [F(1,21) = 5.114, P = 0.0345]. Mean onset and peak latency of CRs exhibited by Aged/Gal rabbits also differed significantly [F(1,21) = 6.120/6.582, P = 0.0220/0.0180, respectively] compared with age-matched controls, resembling more closely CR timing of young drug and control rabbits. Galantamine did not improve acquisition rates in young rabbits compared with age-matched controls. These data indicate that by enhancing nicotinic and muscarinic transmission, galantamine is effective in offsetting the learning deficits associated with decreased cholinergic transmission in the aging brain.

Acetylcholine↗