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Hippocampal CA1 pyramidal cells receive two major excitatory synaptic inputs via the Schaffer collateral (SC) and temporoammonic (TA) pathways. Nicotine promotes induction of long-term potentiation (LTP) in the SC path; however, it is not known whether the modulatory effect of nicotine on LTP induction is pathway-specific. Here we show that nicotine suppresses LTP induction in the TA path. Interestingly, these opposing effects of nicotine were absent or greatly reduced in alpha2 nicotinic acetylcholine receptor (nAChR)-knockout (KO) mice, suggesting that an alpha2-containing nAChR subtype mediates these effects. Optical imaging with a voltage-sensitive dye revealed significantly stronger membrane depolarization in the presence of nicotine in the SC path, facilitating spread of excitatory neural activity along both the somatodendritic and the CA1 proximodistal axes. These effects of nicotine were also absent in alpha2 nAChR-KO mice, suggesting that the enhanced optical signal is related to the nicotine-induced facilitation of LTP induction. In contrast, in the TA path nicotine terminated depolarization more quickly and increased the delayed hyperpolarization in the termination zone of the TA path input. These inhibitory effects of nicotine were absent in alpha2 nAChR-KO mice and, thus, most probably underlie the nicotine-induced suppression of LTP induction. Our results suggest that nicotine influences the local balance between excitation and inhibition, gates LTP, and directs information flow through the hippocampal circuits via the activation of alpha2* nAChRs. These effects of nicotine may represent the cellular basis of nicotine-mediated cognitive enhancement.

Nicotine facilitates the induction of long-term potentiation (LTP) in the hippocampal CA1 region. The present study reveals the potential mechanisms underlying this effect of nicotine. Timed ACh-mediated activation of alpha7 nicotinic acetylcholine receptors (nAChRs) on pyramidal cells is known to promote LTP induction. Nicotine could suppress this timing-dependent mechanism by desensitizing nAChRs. Timed ACh-mediated activation of alpha7 nAChRs on feedforward interneurons can prevent LTP induction by inhibiting pyramidal cells. Nicotine diminished this ACh-mediated inhibition by desensitizing alpha7 nAChRs, thereby reducing the inhibitory influence on pyramidal cells. In addition to these desensitizing effects, nicotine activated presynaptic non-alpha7 nAChRs on feedforward interneurons to decrease the evoked release of gamma-aminobutyric acid (GABA) onto pyramidal cells. Furthermore, nicotine increased the frequency of spontaneous inhibitory postsynaptic currents (IPSCs) in pyramidal cells, and concomitantly caused a reduction in the size of responses to focal GABA application onto the dendrites of pyramidal cells, suggesting that the nicotine-induced increase in interneuronal activity leads ultimately to a use-dependent depression of evoked IPSCs in pyramidal cells. These nicotine-induced suppressions of inhibition of pyramidal cells were accompanied by enhanced N-methyl-D-aspartate (NMDA) responses in pyramidal cells. Thus, our results suggest that nicotine promotes the induction of LTP by diminishing inhibitory influences on NMDA responses while suppressing the ACh-mediated mechanisms. These ACh-independent mechanisms probably contribute to the nicotine-induced cognitive enhancement observed in the presence of cholinergic deficits, such as those in Alzheimer's disease patients.

The nicotinic acetylcholine receptor (nAChR) α 2 subunit was the first neuronal nAChR to be cloned. However, data for the distribution of α 2 mRNA in the rodent exists in only a few studies. Therefore we investigated the expression of α 2 mRNA in the rat and mouse central nervous systems using non-radioactive in situ hybridization histochemistry. We detected strong hybridization signals in cell bodies located in the internal plexiform layer of the olfactory bulb, the interpeduncular nucleus of the midbrain, the ventral and dorsal tegmental nuclei, the median raphe nucleus of the pons, the ventral part of the medullary reticular nucleus, the ventral horn in the spinal cord of both rats and mice, and in a few Purkinje cells of rats, but not of mice. Cells that moderately express α 2 mRNA were localized to the cerebral cortex layers V and VI, the subiculum, the oriens layer of CA1, the medial septum, the diagonal band complex, the substantia innominata, and the amygdala of both animals. They were also located in a few midbrain nuclei of rats, whereas in mice, they were either few or absent in these areas. However, in the upper medulla oblongata, α 2 mRNA was expressed in several large neurons of the gigantocellular reticular nucleus and the raphe magnus nucleus of mice, but not of rats. The data obtained show that a similar pattern of α 2 mRNA expression exists in both rats and mice, with the exception of a few regions, and provide the basis for cellular level analysis. Keywords interpeduncular nucleus; ventral tegmental nucleus; dorsal tegmental nucleus; oriens layer of CA1; internal plexiform layer; in situ hybridizationThe nicotinic acetylcholine receptors (nAChRs) in the rat nervous system are a gene family containing α 2 ), α 3 (Boulter et al., 1986), α 4 (Goldman et al., 1987), α 5 (Boulter et al., 1990) , α 6 (Lamar et al.,1990), α 7 (Seguela et al., 1993), α 9 (Elgoyhen et al.,1994), α 10 (Elgoyhen et al., 2001) , β2 (Deneris et al., 1988), β3 (Deneris et al., 1989), and β4 (Isenberg and Meyer, 1989Duvoisin et al., 1989) (see reviews in Role, 1992;Sargent, 1993;Lindstrom et al., 1998;Lukas et al., 1999;McGehee, 1999). In the mouse nervous system, the expression of α 2-6 and β2-3 was identified using in situ hybridization histochemistry techniques with rat cRNA or oligonucleotide probes (Marks et al., 1992 et al., 1998) and mouse α 2-7 and β2-4 sequences were recently reported (Picciotto et al., 1995;Orr-Urtreger et al., 1995;Watanabe et al., 1998;Kuo, et al., 2002). Combinations of these subunits are thought to form multiple functionally different nAChR subtypes (Luetje and Patrick, 1991), although α 7 and α 9 subunits form functional homooligomers when expressed in Xenopus oocytes (Couturier et al., 1990). The different neuronal nAChR subunit genes are expressed in distinct areas of the central and peripheral nervous systems in the adult rat (Wada et al., 1989 Dineley-Millar and Patrick, 1992;Rust et al., 1994; Le Novere et al., 1996;Flores et al., 1996) and also during development .Data for ...

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