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The Journal of Neuroscience, August 29, 2007, 27(35):9262-9269; doi:10.1523/JNEUROSCI.1843-07.2007

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Neurobiology of Disease
Amyloid ß Protein Modulates Glutamate-Mediated Neurotransmission in the Rat Basal Forebrain: Involvement of Presynaptic Neuronal Nicotinic Acetylcholine and Metabotropic Glutamate Receptors

James H. Chin, Li Ma, David MacTavish, and Jack H. Jhamandas

Department of Medicine (Neurology) and Center for Neuroscience, University of Alberta, Edmonton, Alberta, Canada T6G 2S2

Correspondence should be addressed to Dr. Jack H. Jhamandas, Department of Medicine (Neurology), University of Alberta, 530 Heritage Medical Research Center, Edmonton, Alberta, Canada T6G 2S2. Email: jack.jhamandas{at}ualberta.ca

Amyloid ß (Aß) 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 Aß_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 Aß_1–42 (100 nM), but not Aß_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 Aß_1–42 significantly decreased only the frequency but not amplitude of mEPSCs. Application of dihydro-ß-erythroidine (DHßE) (an antagonist for the 4ß2 subtype of nAChRs) but not -bungarotoxin (an antagonist for the 7 subtype of nAChRs) blocked Aß_1–42-mediated increases in mEPSC frequency. The Aß_1–42-mediated increase in glutamatergic transmission is thus presynaptic and mediated via non-7 AChRs. In contrast, Aß_1–42-mediated decreases in mEPSC frequency could not be antagonized by either DHßE or -bungarotoxin. However, the Aß_1–42 -evoked depression in mEPSC frequency was antagonized by (RS)--methyl-4-carboxyphenyglycine, a nonselective group I/II metabotropic glutamate receptor antagonist. These observations provide further insight into the mechanisms whereby Aß affects synaptic function in the brain and may be relevant in the context of synaptic failure observed in AD.

Key words: amyloid; cholinergic; nicotine; patch clamp; brain slice; miniature EPSCs

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Received Dec. 19, 2006; revised June 4, 2007; accepted June 26, 2007.

Correspondence should be addressed to Dr. Jack H. Jhamandas, Department of Medicine (Neurology), University of Alberta, 530 Heritage Medical Research Center, Edmonton, Alberta, Canada T6G 2S2. Email: jack.jhamandas{at}ualberta.ca

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