Abstract
Prefrontal cortex (PFC) is recognized as an AD-vulnerable region responsible for defects in cognitive functioning. Pyramidal cell (PC) connections are typically facilitating (F) or depressing (D) in PFC. Excitatory post-synaptic potentials (EPSPs) were recorded using patch-clamp from single connections in PFC slices of rats and ferrets in the presence of β-amyloid (Aβ). Synaptic transmission was significantly enhanced or reduced depending on their intrinsic type (facilitating or depressing), Aβ species (Aβ 40 or Aβ 42) and concentration (1–200 nM vs. 0.3–1 μ M). Nanomolar Aβ 40 and Aβ 42 had opposite effects on F-connections, resulting in fewer or increased EPSP failure rates, strengthening or weakening EPSPs and enhancing or inhibiting short-term potentiation [STP: synaptic augmentation (SA) and post-tetanic potentiation (PTP)], respectively. High Aβ 40 concentrations induced inhibition regardless of synaptic type. D-connections were inhibited regardless of Aβ species or concentration. The inhibition induced with bath application was hard to recover by washout, but a complete recovery was obtained with brief local application and prompt washout. Our data suggests that Aβ 40 acts on the prefrontal neuronal network by modulating facilitating and depressing synapses. At higher levels, both Aβ 40 and Aβ 42 inhibit synaptic activity and cause irreversible toxicity once diffusely accumulated in the synaptic environment.
Highlights
In patients and animal models of the early stages of Alzheimer’s Disease (AD), declines in episodic or spatial memory and cognition are correlated with an increase in brain levels of soluble β-amyloid (Aβ) (Lue et al, 1999; Walsh et al, 2002; Rowan et al, 2003)
The studied connections comprise synapses formed between Pyramidal cell (PC) (PC–PC, n = 86 pairs) and those formed by a PC onto an interneuron (PC– IN, n = 14 pairs) (Figure 1)
The neuronal type was identified according to the morphology (PCs and interneurons—mainly basket cells and Marttinoti cells) combined with the firing pattern of action potentials (AP) evoked by depolarizing current steps injected into neuronal somata (Wang et al, 2002, 2006)
Summary
In patients and animal models of the early stages of Alzheimer’s Disease (AD), declines in episodic or spatial memory and cognition are correlated with an increase in brain levels of soluble β-amyloid (Aβ) (Lue et al, 1999; Walsh et al, 2002; Rowan et al, 2003). Synaptic dysfunction as a consequence of diffusible Aβ is inferred from studies showing reduced basal transmission and altered plasticity (Klyubin et al, 2005; Shankar et al, 2008; Minano-Molina et al, 2011). Synapse numbers are reduced early in some AD brain regions (Davies et al, 1987), especially in the prefrontal cortex (PFC) and medial temporal lobe (Morris and Baddeley, 1988). Additional studies in the recent decade indicate that low levels of Aβ peptides could be essential for the modulation of synaptic plasticity (Parihar and Brewer, 2010)
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