Glutamatergic synaptic depression by synthetic amyloid beta-peptide in the medial septum.
The medial septum/diagonal band region, which participates in learning and memory processes via its cholinergic and GABAergic projection to the hippocampus, is one of the structures affected by beta amyloid (betaA) deposition in Alzheimer's disease (AD). The acute effects of betaA (25-35 and 1-40) on action potential generation and glutamatergic synaptic transmission in slices of the medial septal area of the rat brain were studied using current and patch-clamp techniques. The betaA mechanism of action through M1 muscarinic receptors and voltage-dependent calcium channels was also addressed. Excitatory evoked responses decreased (30-60%) in amplitude after betaA (2 microM) perfusion in 70% of recorded cells. However, the firing properties were unaltered at the same concentration. This depression was irreversible in most cases, and was not prevented or reversed by nicotine (5 microM). In addition, the results obtained using a paired-pulse protocol support pre- and postsynaptic actions of the peptide. The betaA effect was blocked by calcicludine (50 nM), a selective antagonist of L-type calcium channels, and also by blocking muscarinic receptors with atropine (5 muM) or pirenzepine (1 microM), a more specific M1-receptor blocker. We show that in the medial septal area this oligomeric peptide acts through calcium channels and muscarinic receptors. As blocking any of these pathways blocks the betaA effects, we propose a joint action through both mechanisms. These results may contribute to a better understanding of the pathophysiology at the onset of AD. This understanding will be required for the development of new therapeutic agents.
Santos-Torres
Julio
J
Departamento de Fisiología y Farmacología, Facultad de Medicina, Instituto de Neurociencias de Castilla y León, Universidad de Salamanca, Salamanca, Spain.
Fuente
Antonio
A
Criado
Jose Maria
JM
Riolobos
Adelaida Sanchez
AS
Heredia
Margarita
M
Yajeya
Javier
J
D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D004594:Electrophysiology; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010890:Pirenzepine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012686:Septal Nuclei / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D014403:Tubocurarine / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D010890:Pirenzepine; D018698:Glutamic Acid; D014403:Tubocurarine