Abeta(1-42) Enhances Neuronal Excitability in the CA1 via NR2B Subunit-Containing NMDA Receptors

Abstract

Neuronal hyperexcitability is a phenomenon associated with early Alzheimer's disease. The underlying mechanism is considered to involve excessive activation of glutamate receptors; however, the exact molecular pathway remains to be determined. Extracellular recording from the CA1 of hippocampal slices is a long-standing standard for a range of studies both in basic research and in neuropharmacology. Evoked field potentials (fEPSPs) are regarded as the input, while spiking rate is regarded as the output of the neuronal network; however, the relationship between these two phenomena is not fully clear. We investigated the relationship between spontaneous spiking and evoked fEPSPs using mouse hippocampal slices. Blocking AMPA receptors (AMPARs) with CNQX abolished fEPSPs, but left firing rate unchanged. NMDA receptor (NMDAR) blockade with MK801 decreased neuronal spiking dose dependently without altering fEPSPs. Activating NMDARs by small concentration of NMDA induced a trend of increased firing. These results suggest that fEPSPs are mediated by synaptic activation of AMPARs, while spontaneous firing is regulated by the activation of extrasynaptic NMDARs. Synaptotoxic Abeta(1-42) increased firing activity without modifying evoked fEPSPs. This hyperexcitation was prevented by ifenprodil, an antagonist of the NR2B NMDARs. Overall, these results suggest that Abeta(1-42) induced neuronal overactivity is not dependent on AMPARs but requires NR2B.

Hippocampal long‐term synaptic depression and memory deficits induced in early amyloidopathy are prevented by enhancing G‐protein‐gated inwardly rectifying potassium channel activity

“…The soluble forms of Aβ 1–42 peptide are pathological species present in AD that are widely used to investigate their contribution to the pathogenesis and progression of the disease (Selkoe & Hardy, ). In vitro acute application of Aβ 1–42 causes hippocampal hyperexcitability (Tamagnini et al, ; Varga et al, ) and deficits in LTP (Eslami et al, ; Kimura et al, ; Lei, Xu, & Li, ). Similarly, different in vivo experiments show that the administration of Aβ 1–42 triggers behavioral deficits because of alterations in neural excitability and LTP process (Kalweit et al, ; Sanchez‐Rodriguez et al, , ).…”

“…We also asked for the mechanism by which an increase in GirK conductance could compensate the excess of neuronal excitability caused by Aβ (Nava‐Mesa et al, ; Tamagnini et al, ; Varga et al, ) and therefore, restore hippocampal synaptic plasticity mechanisms. Present data showed that ML297 was also able to preserve mechanisms needed for LTP induction from the deleterious effects of Aβ 1–42 , most likely by recovering the balance between excitatory and inhibitory neurotransmission in CA3—CA1 synapse acting mainly at post‐synaptic level on pyramidal cells, as we also reported in vivo (Sanchez‐Rodriguez et al, ).…”

Soluble Aβ oligomers impair hippocampal LTP by disrupting glutamatergic/GABAergic balance

“…Administrations of soluble oAβ to cultured neurons (Cuevas et al, 2011), brain slices (Minkeviciene et al,, 2009; Varga et al,2014; Ren et al, 2014) or living animals (Orbán et al,2011; Busche et al, 2012) all induced significant hyperexcitability in hippocampal neurons. These findings are consistent with several AD mouse models in which elevated levels of Aβ are associated with altered neuronal activity, spontaneous seizures, and epileptiform discharges (Palop et al,2007; Brown et al, 2011; Kerrigan et al, 2014).…”

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

“…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].…”