?-Amyloid triggers aberrant over-scaling of homeostatic synaptic plasticity

Alzheimer’s Disease (AD) is characterized by deficits in learning and memory with an eventual loss of higher cognitive functions. Accumulation of ?-amyloid (A?) in the brain is a hallmark of AD and studies have demonstrated that A? can induce synapse dysregulation and altered neuronal activity [26, 32, 37, 54, 58]. Emerging evidence suggests that soluble A? oligomers adversely affect synaptic function, which eventually leads to the cognitive failure associated with AD [36, 43, 48, 58]. A key neuropathobiological hallmark in early AD is the aberrant regulation in synaptic function including AMPA receptor (AMPAR) synaptic accumulation and synaptic plasticity [7, 43]. In vitro studies performed in hippocampal neurons have reported that application of A? peptides, at concentrations below neurotoxic levels, can inhibit LTP induction without affecting basal synaptic transmission [8, 9, 61]. A similar result was shown in vivo, where cerebral injection of naturally secreted A? collected from cells expressing amyloid precursor protein (APP) prevented the stable maintenance of LTP in the hippocampal CA1 region [58]. In vivo injection of A? is reported to facilitate LTD and LTP reversal (depotentiation) in the CA1 region of the hippocampus [32]. These studies have provided great insight into Hebbian plasticity in AD, however the role of A? in homeostatic synaptic plasticity (HSP) remains largely unknown [29].

A major function of HSP is to regulate neuronal activity in a negative feedback manner, thus maintaining neuronal activity or synaptic function [15, 23] within a physiological range after changes in network activity [6, 10, 55, 56]. Under chronic suppression of neuronal activity, HSP is expressed via an increase in synaptic expression of AMPARs producing an up-scaling of AMPAR-mediated miniature post-synaptic currents (mEPSCs). While most studies show inactivity-induced synaptic scaling in cultured neurons [2, 46, 50, 55], HSP is also observed in vivo including in the spinal cord [16, 19, 33, 59] and in the visual cortex [11, 17, 31, 34, 38]. AMPARs are heterotetrameric ion channels consisting of different compositions of the four subunits GluA1–4, and the most common of which are GluA1/GluA2 and GluA2/GluA3 combinations [5, 13]. During the early phase of neural inhibition, a change in GluA2 expression leads to the formation of GluA2-lacking, calcium permeable AMPARs (CP-AMPARs). The production and insertion of CP-AMPARs at the synapse is required for the initiation of HSP. We have recently shown that the brain-enriched microRNA, miR124, causes a selective reduction in GluA2 levels via interaction with its 3’-UTR, leading to CP-AMPAR expression and HSP [24].

Here we report that during inactivity-dependent HSP, either in vitro in cultured neurons with TTX incubation or in vivo in the visual cortex with visual deprivation, application of A? results in an aberrant over-scaling of AMPAR-mediated synaptic currents and surface AMPAR expression. A? incubation or brain injection produces the expression of additional CP-AMPARs under neuronal activity inhibition. The CP-AMPARs are required for the initiation, but not maintenance of HSP. Consistent with this, both in vitro in cultured neurons with TTX incubation, and in vivo in the visual cortex during visual deprivation, application of A? leads to increased miR124 expression and the A?-mediated HSP can be blocked by miR124 suppression. Additionally, we show that A? induces the dissociation of HDAC1 from the inhibitory miR124 transcription factor EVI1, producing an up-regulation of miR124 expression and increased generation of CP-AMPARs. Thus, A? induces an over-response to inactivity-dependent HSP via an upregulation of miR124 and CP-AMPAR expression. Therefore in the presence of A?, neurons adapt their synaptic properties distinctly, which is likely to cause destabilization in neural network operation and brain function in AD.