Nicotinic modulation of synaptic transmission and plasticity in cortico-limbic circuits

Abstract

Nicotine is the principle addictive agent delivered via cigarette smoking. The addictive activity of nicotine is due to potent interactions with nicotinic acetylcholine receptors (nAChRs) on neurons in the reinforcement and reward circuits of the brain. Beyond its addictive actions, nicotine is thought to have positive effects on performance in working memory and short-term attention-related tasks. The brain areas involved in such behaviors are part of an extensive cortico-limbic network that includes relays between prefrontal cortex (PFC) and cingulate cortex (CC), hippocampus, amygdala, ventral tegmental area (VTA) and the nucleus accumbens (nAcc). Nicotine activates a broad array of nAChRs subtypes that can be targeted to pre- as well as peri- and post-synaptic locations in these areas. Thereby, nicotine not only excites different types of neurons, but it also perturbs baseline neuronal communication, alters synaptic properties and modulates synaptic plasticity. In this review we focus on recent findings on nicotinic modulation of cortical circuits and their targets fields, which show that acute and transient activation of nicotinic receptors in cortico-limbic circuits triggers a series of events that affects cognitive performance in a long lasting manner. Understanding how nicotine induces long-term changes in synapses and alters plasticity in the cortico-limbic circuits is essential to determining how these areas interact in decoding fundamental aspects of cognition and reward.

Fig. 1

Model of nicotinic modulation of layer 5 pyramidal neuron in the PFC In layer 5 of the mouse PFC, nicotinic AChRs are expressed on thalamocortical projections (T: yellow ovals on presynaptic profiles) on the cell bodies of low-threshold-spiking GABAergic cells (LTS) and by the regular-spiking-non-pyramidal cells (RSNP). FS cells do not express nAChRs. The glutamatergic inputs from T are increased by nicotine application eliciting an increased excitatory drive to the pyramidal neurons (Pyr), the LTS and the FS components. In addition RSNP cells are directly depolarized by nicotine due to activation of somato-dendritic nAChRs expressed by these cells, without alteration of the excitatory input. Thus, in the PFC nAChR activation results in an increased excitatory drive to the LTS neurons due to both direct activation of somato-dendritic nAChRs and to the indirect enhancement of glutamatergic input to LTS via activation of presynaptic nAChRs. Increased activation of LTS results in increased inhibitory tone from the LTS to layer 5 pyramidal neurons, such that overall effect translates into a net inhibition of the pyramidal cells activity.

Fig. 2

Nicotinic receptors regulate presynaptic gain via both α7*n AChRs and non-α7* nAChRs Presynaptic α7* and non-α7* nAChRs modulate glutamate release via two different mechanisms. Activation of non-α7* nAChRs (A-1) cause depolarization which activates voltage gated calcium channels (VGCC) (2), and elicits fusion and exocytosis (3). (B) Release of higher concentrations of ACh or addition of nicotine activates low affinity α7* nAChRs (4) Upon their activation (5) calcium enters through the channels which can lead to further increases in Ca²⁺ via mobilization from internal Ca²⁺ stores (calciuminduced calcium release (CICR)); 6) The high levels of calcium allow for phosphorylation of Ca²⁺/calmodulin kinase (pCAMKII) (7) which may contribute to the sustained phase of elevated glutamate release (8).