Dual Effect of Beta-Amyloid on α7 and α4β2 Nicotinic Receptors Controlling the Release of Glutamate, Aspartate and GABA in Rat Hippocampus

Abstract

BackgroundWe previously showed that beta-amyloid (Aβ), a peptide considered as relevant to Alzheimer's Disease, is able to act as a neuromodulator affecting neurotransmitter release in absence of evident sign of neurotoxicity in two different rat brain areas. In this paper we focused on the hippocampus, a brain area which is sensitive to Alzheimer's Disease pathology, evaluating the effect of Aβ (at different concentrations) on the neurotransmitter release stimulated by the activation of pre-synaptic cholinergic nicotinic receptors (nAChRs, α4β2 and α7 subtypes). Particularly, we focused on some neurotransmitters that are usually involved in learning and memory: glutamate, aspartate and GABA.Methodology/FindingsWe used a dual approach: in vivo experiments (microdialysis technique on freely moving rats) in parallel to in vitro experiments (isolated nerve endings derived from rat hippocampus). Both in vivo and in vitro the administration of nicotine stimulated an overflow of aspartate, glutamate and GABA. This effect was greatly inhibited by the highest concentrations of Aβ considered (10 µM in vivo and 100 nM in vitro). In vivo administration of 100 nM Aβ (the lowest concentration considered) potentiated the GABA overflow evoked by nicotine. All these effects were specific for Aβ and for nicotinic secretory stimuli. The in vitro administration of either choline or 5-Iodo-A-85380 dihydrochloride (α7 and α4β2 nAChRs selective agonists, respectively) elicited the hippocampal release of aspartate, glutamate, and GABA. High Aβ concentrations (100 nM) inhibited the overflow of all three neurotransmitters evoked by both choline and 5-Iodo-A-85380 dihydrochloride. On the contrary, low Aβ concentrations (1 nM and 100 pM) selectively acted on α7 subtypes potentiating the choline-induced release of both aspartate and glutamate, but not the one of GABA.Conclusions/SignificanceThe results reinforce the concept that Aβ has relevant neuromodulatory effects, which may span from facilitation to inhibition of stimulated release depending upon the concentration used.

Soluble Amyloid-β42 Stimulates Glutamate Release through Activation of the α7 Nicotinic Acetylcholine Receptor

“…Furthermore, Mura and colleagues [8] reported A␤ had a dual effect on the ␣7 and ␣4␤2nAChR in the rat hippocampus. The biggest difference between these two studies was that Mura and colleagues conducted their experiments in awake, freely-behaving rats while our studies were performed in isoflurane anesthetized mice.…”

“…Finally the concentration of A␤ is the largest confounding variable in the literature. Physiological concentrations of A␤ (pM to low nM) have been shown to potentiate neurotransmitter release while supraphysiological concentrations (high nM to M) inhibit neurotransmitter release [8]. While standard practice is to report the concentration of solutions in the glass micropipette, it should be noted that pressure ejection of solutions from a micropipette in vivo act as a point source with the concentration decreasing as the distance increases from the ejection site [18].…”

“…However, at physiological concentrations (pMnM), experimental evidence suggests A␤ has a role in normal brain functions including neurogenesis, longterm potentiation, and neurotransmitter modulation [7][8][9]. A␤ 42 binds to the ␣7 nicotinic acetylcholine receptor (␣7nAChR) with picomolar affinity [10] and activation of this receptor is known to stimulate glutamate release [11].…”

Effects of soluble β-amyloid on the release of neurotransmitters from rat brain synaptosomes

“…However, we cannot completely exclude that small amounts of Aβ oligomers are also present in light of the fact that aggregation is a concentration and time-dependent process (Mura et al, 2012). …”

Amyloid-β Peptide: Dr. Jekyll or Mr. Hyde?

“…Indeed, the acute endogenously-released Aβ induced an increase in the number of synapses and in neurotransmitter release whereas a chronic persistence of Aβ, due to a inhibition of its clearance, induced the opposite effect [62]. Other studies suggest that Aβ may stimulate or inhibit the pre-synaptic release of excitatory neurotransmitters such as aspartate and glutamate depending upon the dose [63]. Taken together, these studies suggest that Aβ and neuronal function are closely related.…”