Our experiments have shown that, in rat prefrontal cortex, 1) nicotine increased sIPSC in layer V pyramidal neurons and the firing rate in layer I interneurons, both of which were disrupted by Aβ; 2) Aβ did not impair nicotinic regulation of sEPSC in layer I interneurons; 3) PKC inhibitors differentially interfered with nicotinic regulation of excitatory or inhibitory transmission, mimicking the effect of Aβ. These results suggest that Aβ selectively impairs nicotinic regulation of inhibitory inputs to cortical pyramidal neurons, which may involve a PKC-dependent mechanism.
Nicotine often has neuron-specific effects in different networks, which are mediated by different nAChR subtypes [21, 34, 35]. In this study, we have found that nicotine enhances both inhibitory inputs to PFC layer V pyramidal neurons and excitatory inputs to layer I interneurons. In the presence of non-α7 nAChR antagonist MEC, both sIPSC and sEPSC are irresponsive to nicotine, suggesting that α4β2 may mediate these effects of nicotine [20, 36]. Nicotine does not alter the excitability of layer V pyramidal neurons, but significantly increases the firing rate of layer I interneurons, an effect mediated by both α7 and non-α7 nAChRs. Involvement of different nAChRs may also suggest distinct roles of nicotine in regulating neuronal functions. In hippocampal cultures, α7 and α4β2 displayed distinct patterns of expression, with α7 preferentially present on the somatodendrites whereas α4β2 distributed on both the axonal and dendritic compartments . Our results are consistent with the finding that presynaptic α4β2 receptors contribute to neurotransmission [38, 39] and both somatodendritic α7 and presynaptic α4β2 receptors modulate neuronal excitability [12, 40, 41].
Both Aβ accumulation and nicotinic deficits occur in the progression of AD [42, 43]. Aβ peptide may alter nicotinic function in several ways. Direct binding of Aβ1–42 to α7 receptors leads to inhibition of channel open probability  and ionic current [43, 45]. However, several lines of evidence suggest that direct inhibition of nAChRs by Aβ might not be enough to explain Aβ-induced impairment of nicotinic functions. In hippocampal interneurons of transgenic mice overexpressing Aβ, α7 nAChRs are still functioning . Aβ is able to elevate presynaptic calcium levels, which could occlude the enhancing effect of nicotine on calcium-dependent transmitter release . Calcium and PKC have been found to be involved in nicotine-facilitated neurotransmission in interneurons [48, 49]. Our results demonstrate that PKC inhibitor has a similar effect on nicotinic regulation of synaptic transmission as Aβ, suggesting that PKC could be an important mediator in Aβ-induced impairment of nAChR functions in AD. It supports the idea that PKC-related intervention might be promising for AD treatment [50–52].
In this study, we have found that nicotinic regulation of interneuron firing and GABAergic inputs to pyramidal neurons are selectively susceptible to Aβ, while nicotinic regulation of excitatory inputs to interneurons is relatively preserved. It suggests that interneuron-mediated inhibition and its excitability are Aβ targets. It is known that inhibitory terminals of fast-spiking interneurons are better equipped to support prolonged transmitter release at a higher frequency in comparison with pyramidal neurons . Electrical and chemical connections of cortical interneurons promote their synchronous firing, thus interneurons play an important role in coordinating cortical activity [54, 55], which is critical for working memory . The Aβ-induced selective impairment of nicotinic regulation of inhibitory inputs to cortical principal neurons could contribute to the dysfunction of neuronal network and the imbalance of inhibition/excitation, leading to interruption of working memory.