Nicotinic modulation of network and synaptic transmission in the immature hippocampus investigated with genetically modified mice

Abstract

The hippocampus, a key structure in learning and memory processes, receives a powerful cholinergic innervation from the septum and contains nicotinic acetylcholine receptors (nAChRs). Early in postnatal development, activation of nAChRs by nicotine or endogenous acetylcholine contributes to enhance synaptic signalling. Here, the patch-clamp technique was used to assess the contribution of α7 and β2-containing (α7 * and β2 * ) nAChRs to nicotine-elicited modulation of GABAergic and glutamatergic activity at the network and single-cell level in the immature hippocampus of wild-type (WT), α7−/− and β2−/− mice. We found that α7 * and β2 * nAChRs were sufficient to modulate nicotine-induced increase in frequency of spontaneously occurring giant depolarizing potentials (GDPs), which are generated at the network level by the synergistic action of glutamate and depolarizing GABA, and thought to play a crucial role in neuronal wiring. However, α7 * but not β2 * receptors were essential in nicotine-induced increase of interictal discharge frequency recorded after postnatal day 3 in the presence of bicuculline, when GABA shifted from the depolarizing to the hyperpolarizing direction. To correlate these observations with nicotine-elicited changes in synaptic transmission, we recorded spontaneous GABAergic and glutamatergic postsynaptic currents in pyramidal cells and interneurons localized in stratum oriens, stratum pyramidale and stratum radiatum, in slices obtained from WT and knock-out animals. We found that early in postnatal life α7 * and β2 * nAChRs exert a fine regional modulation of GABAergic and glutamatergic transmission that underlies nicotine-elicited changes in network synchronization.

Nicotine Modulates the Renin–Angiotensin System of Cultured Neurons and Glial Cells from Cardiovascular Brain Areas of Wistar Kyoto and Spontaneously Hypertensive Rats

“…Thus, it is possible to hypothesize that increased AT 2 R observed in hypertensive animals might be involved in other brain mechanism, such as neuroprotection. In support of this, we have observed that nicotine, known to be involved in neuroprotection (Belluardo et al 2000), brain development (Le Magueresse et al 2006), and neuronal plasticity (Bancroft and Levin 2000), increased AT 2 R binding only in neurons from SHR. Furthermore, SHR might be more susceptible to brain damages in uterus because of hypertension of their progenitor (Fredriksson et al 1989), which might correlate with increased AT 2 R binding.…”

Role of endogenous nicotinic signaling in guiding neuronal development

“…This has been well-documented for the retina and spinal cord where it helps direct target selection and synapse formation (20)(21)(22)(23). Spontaneous nicotinic excitation also contributes to the giant depolarizing potentials reported for neurons in the developing hippocampus (9,24,25). This pervasiveness of nicotinic excitation at late embryonic and early postnatal stages raises questions about the role of nicotinic input in neurodevelopment.…”

Sequential Interplay of Nicotinic and GABAergic Signaling Guides Neuronal Development

“…Repetitive spontaneous waves of excitation, driven initially by nicotinic activity and dependent on GABA/glycine, spread throughout the retina and spinal cord during development and influence the pattern of connections formed (21)(22)(23)(24). The developing hippocampus also has spontaneous waves dependent on GABAergic excitation and subject to nicotinic modulation (25,26).…”