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

Amyloid beta(A beta) 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 ofA beta(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 A beta(1-42) (100 nM), but not A beta(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 A beta(1-42) significantly decreased only the frequency but not amplitude of mEPSCs. Application of dihydro-beta-erythroidine (DH beta E) (an antagonist for the alpha 4 beta 2 subtype of nAChRs) but not alpha-bungarotoxin (an antagonist for the alpha 7 subtype of nAChRs) blocked A beta(1-42)-mediated increases in mEPSC frequency. The A beta(1-42)-mediated increase in glutamatergic transmission is thus presynaptic and mediated via non-alpha 7 AChRs. In contrast, A beta(1-42)-mediated decreases in mEPSC frequency could not be antagonized by either DH beta E or alpha-bungarotoxin. However, the A beta(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 A beta affects synaptic function in the brain and may be relevant in the context of synaptic failure observed in AD.