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

Abstract

Amyloid β (Aβ) 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 Aβ1-42 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 Aβ1-42 (100 nM), but not Aβ42-1 (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 Aβ1-42 significantly decreased only the frequency but not amplitude of mEPSCs. Application of dihydro-β-erythroidine (DHβE) (an antagonist for the α4β2 subtype of nAChRs) but not α-bungarotoxin (an antagonist for the α7 subtype of nAChRs) blocked Aβ1-42-mediated increases in mEPSC frequency. The Aβ1-42-mediated increase in glutamatergic transmission is thus presynaptic and mediated via non-α7 AChRs. In contrast, Aβ1-42-mediated decreases in mEPSC frequency could not be antagonized by either DHβE or α-bungarotoxin. However, the Aβ1-42-evoked depression in mEPSC frequency was antagonized by (RS)-α-methyl-4-carboxyphenyglycine, a nonselective group I/II metabotropic glutamate receptor antagonist. These observations provide further insight into the mechanisms whereby Aβ affects synaptic function in the brain and may be relevant in the context of synaptic failure observed in AD. Copyright © 2007 Society for Neuroscience.