Amyloid beta protein modulates glutamate-mediated neurotransmission in the rat basal forebrain: involvement of presynaptic neuronal nicotinic acetylcholine and metabotropic glutamate receptors

• Published in: The Journal of neuroscience Vol. 27; no. 35; pp. 9262 - 9269
• Main Authors: Chin, James H, Ma, Li, MacTavish, David, Jhamandas, Jack H
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 29.08.2007
• Subjects: 6-Cyano-7-nitroquinoxaline-2,3-dione - pharmacology; Amyloid beta-Peptides - pharmacology; Animals; Antibodies, Monoclonal - pharmacokinetics; Carbocyanines - pharmacokinetics; Cholinergic Agents - pharmacokinetics; Diagonal Band of Broca - cytology; Dihydro-beta-Erythroidine - pharmacology; Electric Stimulation - methods; Excitatory Amino Acid Antagonists - pharmacology; Excitatory Postsynaptic Potentials - drug effects; Excitatory Postsynaptic Potentials - physiology; Excitatory Postsynaptic Potentials - radiation effects; Glutamic Acid - pharmacology; In Vitro Techniques; N-Glycosyl Hydrolases - pharmacokinetics; Neurons - drug effects; Nicotinic Antagonists - pharmacology; Patch-Clamp Techniques - methods; Peptide Fragments - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate - physiology; Receptors, Nicotinic - physiology; Ribosome Inactivating Proteins, Type 1; Saporins
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1843-07.2007

Amyloid beta (Abeta) protein, a 39-43 amino acid peptide deposited in brains of individuals with Alzheimer's disease (AD), has been shown to interact directly with a number of receptor targets including neuronal nicotinic acetylcholine receptors (nAChRs) and glutamate receptors. In this study, we investigated the synaptic effects of Abeta(1-42) on glutamate-mediated neurotransmission in the diagonal band of Broca (DBB), a cholinergic basal forebrain nucleus. Glutamatergic miniature EPSCs (mEPSCs) were recorded using whole-cell patch-clamp recordings from identified cholinergic DBB neurons in rat forebrain slices. In 54% of DBB neurons, bath application of Abeta(1-42) (100 nM), but not Abeta(42-1) (inverse fragment), significantly increased the frequency of mEPSCs without affecting amplitude or kinetic parameters (rise or decay time). In 32% of DBB neurons, bath application of Abeta(1-42) significantly decreased only the frequency but not amplitude of mEPSCs. Application of dihydro-beta-erythroidine (DHbetaE) (an antagonist for the alpha4beta2 subtype of nAChRs) but not alpha-bungarotoxin (an antagonist for the alpha7 subtype of nAChRs) blocked Abeta(1-42)-mediated increases in mEPSC frequency. The Abeta(1-42)-mediated increase in glutamatergic transmission is thus presynaptic and mediated via non-alpha7 AChRs. In contrast, Abeta(1-42)-mediated decreases in mEPSC frequency could not be antagonized by either DHbetaE or alpha-bungarotoxin. However, the Abeta(1-42)-evoked depression in mEPSC frequency was antagonized by (RS)-alpha-methyl-4-carboxyphenyglycine, a nonselective group I/II metabotropic glutamate receptor antagonist. These observations provide further insight into the mechanisms whereby Abeta affects synaptic function in the brain and may be relevant in the context of synaptic failure observed in AD.