Regulation of hippocampal inhibitory circuits by nicotinic acetylcholine receptors

Abstract

The hippocampal network comprises a large variety of locally connected GABAergic interneurons exerting a powerful control on network excitability and which are responsible for the oscillatory behaviour crucial for information processing. GABAergic interneurons receive an important cholinergic innervation from the medial septum-diagonal band complex of the basal forebrain and are endowed with a variety of muscarinic and nicotinic acetylcholine receptors (mAChRs and nAChRs) that regulate their activity. Deficits in the cholinergic system lead to the impairment of high cognitive functions, which are particularly relevant in neurodegenerative pathologies such as Alzheimer's and Parkinson's diseases as well as in schizophrenia. Here, we highlight some recent advances in the mechanisms by which cholinergic signalling via nAChRs regulates local inhibitory circuits in the hippocampus, early in postnatal life and in adulthood. We also discuss recent findings concerning the functional role of nAChRs in controlling short- and long-term modifications of synaptic efficacy. Insights into these processes may provide new targets for the therapeutic control of pathological conditions associated with cholinergic dysfunctions.

Figure 1. Different regulation of GDPs and interictal discharges by nAChRs

A, representative traces recorded at P5–P6 from CA1 pyramidal neurons in hippocampal slices obtained from WT, α7^-/- and β2^-/- mice, respectively, in control conditions and in the presence of nicotine (1 μm). The inset above the traces represents a GDP at an expanded time scale. B, each column represents nicotine-induced changes of GDP frequency as a percentage of control (dashed line); n = 6–12. C and D, as in A and B but for interictal discharges induced by bicuculline at P9–P10 (see the inset above the traces); n = 3–13; *P < 0.05; **P < 0.01. While nicotine enhanced GDPs frequency via activation of α7- and β2-containing nAChRs, it increased the frequency of interictal discharges only via α7 nAChRs, indicating a different distribution of nAChRs between GABAergic interneurons and principal cells. Modified from Le Magueresse et al. 2006.

Figure 2. Simplified view of the expression of different nAChR subtypes on pyramidal cells and GABAergic interneurons present in the CA1 hippocampal region

SLM, stratum lacunosum moleculare; SR, stratum radiatum; SP, stratum pyramidale; SO, stratum oriens; PY, pyramidal cells; PV+, parvalbumin-positive; CCK+, cholecystokinin-positive; AA, axo-axonic interneurons; O-LM, oriens-lacunosum moleculare; PPA, perforant path-associated lacunosum moleculare or lacunosum moleculare-radiatum interneurons; NG, neurogliaform cell. Dashed lines represent glutamatergic terminals from pyramidal cells (yellow) or from GABAergic interneurons (blue).

Figure 3. Activation of nAChRs by nicotine or endogenously released ACh reduces the firing rate of O-LM interneurons

A, camera lucida reconstruction of a O-LM cell. B, puff application of nicotine induces a fast inward current followed by a slow one. In the presence of αBGTx (100 nm, middle) a slow component is unveiled. Pressure application of choline to another cell induces a fast response. C, regular spiking interneuron in control and after bath application of nicotine. D, each column represents the mean spike frequency values (expressed as percentage of control, dashed line), obtained in the presence of nicotine (n = 21) and nicotine plus MLA (n = 16) or DHβE (n = 16). E, a regular spiking neuron recorded before (Control) and immediately after delivering one train of high-frequency stimuli (2 s duration at 25 Hz) to cholinergic fibres in the alveus (in the presence of atropine). F, as in E but in the presence of a high (50 μm) concentration of DHβE. G, each column represents the mean spike frequency values obtained after stimulation of cholinergic fibres in the absence (open, n = 8) or in the presence (filled, n = 8) of DHβE and expressed as percentage of control (dashed line). *P < 0.05; ***P < 0.001. Modified from Griguoli et al. 2009.