Aβ impairs nicotinic regulation of inhibitory synaptic transmission and interneuron excitability in prefrontal cortex

Accumulation of β-amyloid (Aβ) and cholinergic deficiency are two prominent features of Alzheimer's disease (AD). To understand how Aβ-induced dysfunction of the nicotinic system may contribute to cognitive impairment in AD, we examined the effect of Aβ on nicotinic regulation of synaptic transmission and neuronal excitability in prefrontal cortex (PFC), a brain region critical for cognitive processes.

We found that activation of nicotinic acetylcholine receptors (nAChRs) with nicotine increased the inhibitory postsynaptic currents recorded in PFC pyramidal neurons, which was associated with the nicotine-induced increase in the excitability of PFC layer I GABAergic interneurons. Both effects of nicotine were disrupted by Aβ. However, Aβ did not impair nicotinic regulation of excitatory neurotransmission in PFC interneurons. The nicotinic effect on synaptic inhibition was also lost in transgenic mice with five familial Alzheimer's disease mutations. Inhibiting PKC attenuated nicotinic regulation of inhibitory, but not excitatory, neurotransmission.

Our study suggests that Aβ selectively impairs nicotinic regulation of inhibitory inputs to PFC pyramidal neurons, which might be due to its interference with PKC activation. Thus, in the PFC circuits of AD, the balance between inhibition and excitation under the control of nAChRs may be disturbed by Aβ.