Regulation of synaptic transmission and plasticity by neuronal nicotinic acetylcholine receptors

Abstract

Nicotinic acetylcholine receptors (nAChRs) are widely expressed throughout the central nervous system and participate in a variety of physiological functions. Recent advances have revealed roles of nAChRs in the regulation of synaptic transmission and synaptic plasticity, particularly in the hippocampus and midbrain dopamine centers. In general, activation of nAChRs causes membrane depolarization and directly and indirectly increases the intracellular calcium concentration. Thus, when nAChRs are expressed on presynaptic membranes their activation generally increases the probability of neurotransmitter release. When expressed on postsynaptic membranes, nAChR-initiated calcium signals and depolarization activate intracellular signaling mechanisms and gene transcription. Together, the presynaptic and postsynaptic effects of nAChRs generate and facilitate the induction of long-term changes in synaptic transmission. The direction of hippocampal nAChR-mediated synaptic plasticity - either potentiation or depression - depends on the timing of nAChR activation relative to coincident presynaptic and postsynaptic electrical activity, and also depends on the location of cholinergic stimulation within the local network. Therapeutic activation of nAChRs may prove efficacious in the treatment of neuropathologies where synaptic transmission is compromised, as in Alzheimer's or Parkinson's disease.

Fig. 1

Transmembrane topology and pentameric structure of nAChRs. (A) nAChRs consist of four transmembrane domains (M1 through M4) with extracellular C- and N-termini. (B) Subunits are assembled into pentamers that include a water-filled cation-permeable pore. The most common nAChRs in the brain are hetero-oligomeric α4β2 nAChRs and homo-oligomeric α7 nAChRs. The recognized ACh binding sites are indicated by filled black squares.

Fig. 2

Temporal-dependence of nAChR activation for hippocampal synaptic plasticity. (A) Illustration of the experimental setup for experiments shown in panels (B) through (E). Whole-cell patch recordings were obtained from CA1 pyramidal somata, with activation of Schaffer collateral afferents in stratum radiatum. A puffer pipette delivered brief pulses of ACh (in the presence of atropine) to the pyramidal neuron’s dendrites. All postsynaptic potentials (PSPs) were normalized to baseline. (B) ACh-induced APs that preceded HFS of the Schaffer collaterals by ≥ 10 sec did not affect STP. (C) In contrast, ACh-induced APs that terminated 1–5 sec prior to HFS boosted STP to LTP. (D) If the APs terminated < 1 sec before HFS, then LTD resulted. (E) If the ACh-evoked APs followed HFS then there was no effect on STP. (F) Summary of the findings in (B) through (E). The normalized PSPs from the last 15 min of post-HFS recording were averaged and then plotted against the time between the end of ACh application and the onset of HFS. Negative time values correspond to the interval between the last ACh-induced AP and the onset of HFS. Positive time values correspond to the interval between the end of HFS and the onset of the first ACh-induced AP. The curve drawn through the data points indicates the general trend of the data. Arrows indicate timing of HFS for all panels. Adapted with permission from [92] (copyright 2005 by the Society for Neuroscience).

Fig. 3

Spatial-dependence of nAChR activation for hippocampal synaptic plasticity. (A) Illustration of the experimental setup for experiments shown in panels (B) and (C). The puffer pipette applies ACh to a GABAergic interneuron neighboring the pyramidal neuron. All PSPs were normalized to baseline. (B, C) HFS-evoked LTP (B) was prevented by activating inhibitory interneurons with ACh (C). Arrows indicate timing of HFS for all panels. Adapted with permission from [81] (copyright 2001 by Cell Press).

Fig. 4

Synaptic plasticity in the VTA. (A) Dopamine levels are elevated in the nucleus accumbens of rats for more than two hours following a single i.p. injection of 0.6 mg/kg nicotine. (B) Bath applied nicotine increases the frequency of AP discharge in dopaminergic neurons mainly via β2* nAChRs. (C) Bath applied nicotine increases the frequency of spontaneous EPSCs (sEPSCs) mainly via presynaptic α7* nAChRs. The coincidence of postsynaptic and presynaptic activation by nicotine is sufficient to induce LTP of the glutamatergic synapses. (D) The frequency of spontaneous IPSCs (sIPSCs) first increases, and then decreases below baseline following desensitization of β2* nAChRs on the somata of GABAergic neurons. The decrease in IPSC frequency indirectly enhances the glutamatergic excitation of dopamine neurons. Adapted with permission from [140, 144] (copyright 1997 by Nature Publishing Group [144] and copyright 2004 by Cold Spring Harbor Laboratory Press [140]).