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1.  Nicotinic Receptor Mediated Filtering of Mitral Cell Responses to Olfactory Nerve Inputs Involves the α3β4 Subtype 
The Journal of Neuroscience  2012;32(9):3261-3266.
Acetylcholine plays a major role in the processing of sensory inputs. Cholinergic input to the mammalian olfactory bulb modulates odor discrimination and perceptual learning by mechanisms that are yet to be elucidated. We have used the mouse olfactory bulb in order to examine the role of nicotinic acetylcholine receptors (nAChRs) in regulating the responses of mitral cells (MCs), the output neurons of the olfactory bulb, to olfactory nerve input. We show that acetylcholine activates α3β4* nAChRs (* denotes possible presence of other subunits) on MCs leading to their excitation. Despite depolarizing MCs directly, the net effect of nAChR activation is to suppress olfactory nerve-evoked responses in these cells via activity-dependent, feedback GABAergic mechanisms. Our results indicate that nAChRs gate incoming olfactory nerve input wherein weak input stimuli are filtered out, while strong stimuli are transmitted via the MCs. Based on our observations, we provide a mechanistic model for the sharpening of mitral cell receptive fields by nAChRs, which could aid in odor discrimination and perceptual learning.
doi:10.1523/JNEUROSCI.5024-11.2012
PMCID: PMC3306821  PMID: 22378897
2.  A Transgenic Mouse Model Reveals Fast Nicotinic Transmission in Hippocampal Pyramidal Neurons 
The European journal of neuroscience  2011;33(10):1786-1798.
The relative contribution, to brain cholinergic signaling, by synaptic- and diffusion-based mechanisms remains to be elucidated. In this study, we examined the prevalence of fast nicotinic signaling in the hippocampus. We describe a mouse model where cholinergic axons are labeled with the tauGFP fusion protein driven by the choline acetyltransferase (ChAT) promoter. The model provides for the visualization of individual cholinergic axons at greater resolution than other available models and techniques, even in thick, live, slices. Combining calcium imaging and electrophysiology, we demonstrate that local stimulation of visualized cholinergic fibers results in rapid EPSCs mediated by the activation of α7-subunit containing nicotinic receptors (α7-nAChRs) on CA3 pyramidal neurons. These responses were blocked by the α7-nAChR antagonist methyllycaconitine (MLA) and potentiated by the receptor specific allosteric modulator 1-(5-chloro-2,4- dimethoxy-phenyl)-3-(5-methyl-isoxanol-3-yl)-urea (PNU-120596).
Our results suggest, for the first time, that synaptic nAChRs can modulate pyramidal cell plasticity and development. Fast nicotinic transmission might play a greater role in cholinergic signaling than previously assumed. We provide a model for the examination of synaptic properties of basal forebrain cholinergic innervation in the brain.
doi:10.1111/j.1460-9568.2011.07671.x
PMCID: PMC3095690  PMID: 21501254
cholinergic; acetylcholine; tauGFP; choline acetyltransferase; synaptic transmission
3.  Activity-Dependent Changes in Cholinergic Innervation of the Mouse Olfactory Bulb 
PLoS ONE  2011;6(10):e25441.
The interplay between olfactory activity and cholinergic modulation remains to be fully understood. This report examines the pattern of cholinergic innervation throughout the murine main olfactory bulb across different developmental stages and in naris-occluded animals. To visualize the pattern of cholinergic innervation, we used a transgenic mouse model, which expresses a fusion of the microtubule-associated protein, tau, with green fluorescence protein (GFP) under the control of the choline acetyltransferase (ChAT) promoter. This tau-GFP fusion product allows for a remarkably vivid and clear visualization of cholinergic innervation in the main olfactory bulb (MOB). Interestingly, we find an uneven distribution of GFP label in the adult glomerular layer (GL), where anterior, medial, and lateral glomerular regions of the bulb receive relatively heavier cholinergic innervation than other regions. In contrast to previous reports, we find a marked change in the pattern of cholinergic innervation to the GL following unilateral naris occlusion between the ipsilateral and contralateral bulbs in adult animals.
doi:10.1371/journal.pone.0025441
PMCID: PMC3203864  PMID: 22053179
4.  Functional Distribution of Nicotinic Receptors in CA3 Region of the Hippocampus 
Nicotinic acetylcholine receptor (nAChR) modulation of a number of parameters of synaptic signaling in the brain has been demonstrated. It is likely that effects of nicotine are due to its ability to modulate network excitability as a whole. A pre-requisite to understanding the effects of nicotine on network properties is the elucidation of functional receptors. We have examined the distribution of functional nAChRs in the dentate gyrus granule cells and the CA3 region of the mammalian hippocampus using calcium imaging from acute slices. Our results demonstrate the presence of functional nAChRs containing the α7 subunit (α7-nAChRs) on mossy fiber boutons, CA3 pyramidal cells, and on astrocytes. In addition, both CA3 interneurons and granule cells show nicotinic signals. Our study suggests that functional nicotinic receptors are widespread in their distribution and that calcium imaging might be an effective technique to examine locations of these receptors in the mammalian brain.
doi:10.1007/s12031-009-9266-8
PMCID: PMC2871704  PMID: 19693709
nAChRs; CA3 pyramidal neurons; Granule cells; Nicotinic; Hippocampus
5.  Glial–Neuronal Interactions—Implications for Plasticity and Drug Addiction 
The AAPS Journal  2009;11(1):123-132.
Among neuroscientists, astrocytes have for long played Cinderella to their neuron stepsisters. While the importance of glia in regulating brain activity was predicted by Ramon y Cajal more than a century ago (Garcia-Marin et al., Trends. Neurosci. 30:479–787, 2007), these cells, until recently, have been thought to play mainly a passive part in synaptic signaling. Results obtained over the last decade have begun to suggest otherwise. Experiments carried out in a number of labs have shown that glial cells, especially astrocytes, directly participate in synaptic signaling and potentially regulate synaptic plasticity and network excitability. The presence of signaling pathways on astrocytes that are analogous to those at presynaptic terminals suggests a role for these cells in network plasticity. Findings that the same signaling pathways can be activated by receptors for drugs of abuse present on astrocytes suggest a role for these cells in the addictive process. In this review, we summarize current understanding of astrocytic role in synaptic signaling and suggest that a complete understanding of the process of addiction requires a better understanding of the functional role of these cells.
doi:10.1208/s12248-009-9085-4
PMCID: PMC2664886  PMID: 19238557
astrocyte; calcium; gliotransmission; nicotinic; synapse; tripartite synapse
6.  Nicotinic Receptors: Role in Addiction and Other Disorders of the Brain 
Nicotine, the addictive component of cigarette smoke has profound effects on the brain. Activation of its receptors by nicotine has complex consequences for network activity throughout the brain, potentially contributing to the addictive property of the drug. Nicotinic receptors have been implicated in psychiatric illnesses like schizophrenia and are also neuroprotective, potentially beneficial for neurodegenerative diseases. These effects of nicotine serve to emphasize the multifarious roles the drug, acting through multiple nicotinic acetylcholine receptor subtypes. The findings also remind us of the complexity of signaling mechanisms and stress the risks of unintended consequences of drugs designed to combat nicotine addiction.
PMCID: PMC2817963  PMID: 20148179
Nicotine; drug abuse; network; hedonic homeostasis; Calcium
7.  Glial–Neuronal Interactions—Implications for Plasticity and Drug Addiction 
The AAPS journal  2009;11(1):123-132.
Among neuroscientists, astrocytes have for long played Cinderella to their neuron stepsisters. While the importance of glia in regulating brain activity was predicted by Ramon y Cajal more than a century ago (Garcia-Marin et al., Trends. Neurosci. 30:479–787, 2007), these cells, until recently, have been thought to play mainly a passive part in synaptic signaling. Results obtained over the last decade have begun to suggest otherwise. Experiments carried out in a number of labs have shown that glial cells, especially astrocytes, directly participate in synaptic signaling and potentially regulate synaptic plasticity and network excitability. The presence of signaling pathways on astrocytes that are analogous to those at presynaptic terminals suggests a role for these cells in network plasticity. Findings that the same signaling pathways can be activated by receptors for drugs of abuse present on astrocytes suggest a role for these cells in the addictive process. In this review, we summarize current understanding of astrocytic role in synaptic signaling and suggest that a complete understanding of the process of addiction requires a better understanding of the functional role of these cells.
doi:10.1208/s12248-009-9085-4
PMCID: PMC2664886  PMID: 19238557
astrocyte; calcium; gliotransmission; nicotinic; synapse; tripartite synapse
8.  Action Potential-Independent and Nicotinic Receptor-Mediated Concerted Release of Multiple Quanta at Hippocampal CA3–Mossy Fiber Synapses 
Presynaptic action potential-independent transmitter release is a potential means of information transfer across synapses. We show that in the hippocampal mossy fiber boutons, activation of the α7-subtype of nicotinic acetylcholine receptors (α7-nAChRs) results in a large increase in the amplitude of spontaneous events, resulting from concerted release of multiple quanta from the mossy fiber boutons. This amplitude increase is abolished at low temperatures. Activation of α7-nAChRs causes a rise in intraterminal calcium at mossy fiber boutons, involving ryanodine receptors. Regulation of concerted release requires the subsequent activation of presynaptic calcium/calmodulin-dependent protein kinase II (CaMKII). Activation of CaMKII is required to drive presynaptic action potential-independent transmission at the mossy fiber–CA3 pyramidal cell synapse. The effects of α7-nAChR activation are mediated by biologically relevant doses of nicotine. Our results demonstrate a novel form of synaptic plasticity mediated by presynaptic α7-nAChRs and store calcium that is temporally different and might respond to a different history of synaptic activity than that mediated by incoming action potentials.
doi:10.1523/JNEUROSCI.5407-07.2008
PMCID: PMC2696816  PMID: 18322100
nicotine; addiction; synaptic plasticity; synaptic vesicle release; acetylcholine receptor; synaptic communication; multivesicular; mEPSCs

Results 1-8 (8)