Alterations in the balance of protein kinase and phosphatase activities and age-related impairments of synaptic transmission and long-term potentiation

• Published in: Hippocampus Vol. 12; no. 6; pp. 787 - 802
• Main Authors: Hsu, Kuei-Sen, Huang, Chiung-Chun, Liang, Ying-Ching, Wu, Huang-Ming, Chen, Yea-Lin, Lo, Shiow-Win, Ho, Wen-Chia
• Format: Journal Article
• Language: English
• Published: New York Wiley Subscription Services, Inc., A Wiley Company 2002
• Subjects: Action Potentials - drug effects; Action Potentials - physiology; Afferent Pathways - drug effects; Afferent Pathways - enzymology; Afferent Pathways - physiopathology; aging; Aging - metabolism; Animals; Avoidance Learning - drug effects; Avoidance Learning - physiology; Electric Stimulation; Excitatory Postsynaptic Potentials - drug effects; Excitatory Postsynaptic Potentials - physiology; hippocampus; Hippocampus - enzymology; Hippocampus - pathology; Hippocampus - physiopathology; long-term depression; long-term potentiation; Long-Term Potentiation - drug effects; Long-Term Potentiation - physiology; Male; Memory Disorders - enzymology; Memory Disorders - physiopathology; Neural Inhibition - drug effects; Neural Inhibition - physiology; Neurons - drug effects; Neurons - enzymology; Phosphoprotein Phosphatases - antagonists & inhibitors; Phosphoprotein Phosphatases - metabolism; Protein Kinase Inhibitors; Protein Kinases - metabolism; Rats; Rats, Sprague-Dawley; synaptic plasticity; Synaptic Transmission - drug effects; Synaptic Transmission - physiology
• ISSN: 1050-9631; 1098-1063
• DOI: 10.1002/hipo.10032

Aging is associated with an impaired ability to maintain long‐term potentiation (LTP), but the underlying cause of the impairment remains unclear. To gain a better understanding of the cellular and molecular mechanisms responsible for this impairment, the synaptic transmission and plasticity were studied in the CA1 region of hippocampal slices from adult (6–8 months) and poor‐memory (PM)‐aged (23–24 months) rats. The one‐way inhibitory avoidance learning task was used as the behavioral paradigm to screen PM‐aged rats. With intracellular recordings, CA1 neurons of PM‐aged rats exhibited a more hyperpolarized resting membrane potential, reduced input resistance, and increased amplitude of afterhyperpolarization and spike threshold, compared with those in adult rats. Although a reduction in the size of excitatory synaptic response was observed in PM‐aged rats, no obvious differences were found between adult and PM‐aged rats in the pharmacological properties of excitatory synaptic response, paired‐pulse facilitation, or frequency‐dependent facilitation, which was tested with trains of 10 pulses at 1, 5, and 10 Hz. Slices from the PM‐aged rats displayed significantly reduced early‐phase long‐term potentiation (E‐LTP) and late‐phase LTP (L‐LTP), and the entire frequency‐response curve of LTP and LTD is modified to favor LTD induction. The susceptibility of time‐dependent reversal of LTP by low‐frequency afferent stimulation was also facilitated in PM‐aged rats. Bath application of the protein phosphatase inhibitor, calyculin A, enhanced synaptic response in slices from PM‐aged, but not adult, rats. In contrast, application of the cAMP‐dependent protein kinase inhibitors, Rp‐8‐CPT‐cAMPS and KT5720, induced a decrease in synaptic transmission only in slices from the adult rats. Furthermore, the selective β‐adrenergic receptor agonist, isoproterenol, and pertussis toxin‐sensitive G‐protein inhibitor, N‐ethylmaleimide, effectively restored the deficit in E‐LTP and L‐LTP of PM‐aged rats. These results demonstrate that age‐related impairments of synaptic transmission and LTP may result from alterations in the balance of protein kinase/phosphatase activities. Hippocampus 2002;12:787–802. © 2002 Wiley‐Liss, Inc.