The neurons release additional GABA, activating presynaptic GABAB receptors on the excitatory inputs to pyramidal neurons, which diminish the release of glutamate onto the pyramidal neurons (Figure 2)
We now realize that acetylcholine liberated from cholinergic nerve terminals often activates both nAChRs and muscarinic receptors
A possible candidate is choline, which, in addition to its other development roles, activates alpha7 nAChRs at levels several fold higher than acetylcholine
As we will see below, the mystery of somatodendritic nAChRs can also be resolved by the sensitivity of alpha7 nAChRs to constant levels of another agonist, choline
A major subtype in the brain is alpha4beta2; the (alpha42beta23) stoichiometry exhibits at least 10-fold-higher sensitivity than (alpha43beta22), so that only the former has the high sensitivity (HS) that allows activation at nicotine concentrations in the 0.1–1 mM range, produced by moderate tobacco use and by the various nicotine replacement therapies
alpha7 nAChRs also respond to nicotine concentrations roughly an order of magnitude higher than alpha42beta23, and alpha7 nAChRs have high Ca2+ permeability resembling that of NMDA receptors
While it is not yet possible to know precisely how well a7 nAChRs are activated by smoked nicotine, one can reasonably hypothesize that the patients’ higher dose of nicotine activates alpha7 nAChRs (Adler et al., 1993; Papke and Thinschmidt, 1998; Royal College of Physicians, 2007)
Evidence thus far indicates that the lynx family is regulated in response to relatively strong perturbations: downregulation in NKCC1 knockout mice (Pfeffer et al., 2009), in adenylyl cyclase mutant mice (Wieczorek et al., 2010), and by alpha7 nAChR blockade (Hruska et al., 2009), whereas it is upregulated at the close of the critical period in the visual cortex, and by nicotine in the lung (Sekhon et al., 2005)
Nicotine both activates and desensitizes nAChRs in midbrain dopaminergic neurons (Brodie, 1991; Pidoplichko et al., 1997), and the pleasurable effects associated with nicotine intake occur in large part via the mesolimbic dopaminergic reward system (Corrigall et al., 1992; Koob and Volkow,2010)
This puzzle does not yet have a complete answer, but it is clear that chronic nicotine increases the number of nAChRs themselves (Marks et al., 1983; Schwartz and Kellar, 1983)
At the level of whole brain, chronic nicotine causes selective upregulation of nAChRs among major brain regions. Upregulation occurs in cortex, midbrain, and hypothalamus, but not in thalamus or cerebellum (Pauly et al., 1991; Marks et al., 1992; Nguyen et al., 2003; Nashmi et al., 2007; Doura et al., 2008)
However, it is not known whether the nicotine-enhanced cognitive performance exceeds the level that would occur if the person had never begun to smoke, or after remaining abstinent for one year (the usual criterion for successful smoking cessation) (Levin et al., 2006)
Chronic or acute nicotine enhances LTP in several regions of hippocampus, especially dentate gyrus (Nashmi et al., 2007; TangandDani, 2009;Pentonet al., 2011)
For instance, dopamine increases in the extended amygdala during stress, fear, and nicotine withdrawal (Inglis and Moghaddam, 1999; Pape, 2005; Grace et al., 2007; Gallagher et al., 2008; Koob, 2009; Marcinkiewcz et al., 2009)
Chronic nicotine upregulates alpha4* nAChRs in dopaminergic presynaptic terminals, apparently leading to increased resting dopamine release from those terminals
In the medial perforant path, which mainly arises from layer II stellate cells, chronic nicotine upregulates alpha4beta2* nAChRs
In midbrain, chronic nicotine treatment elicits a general increase in alpha4beta2* nAChRs in GABAergic neurons, but only in axon terminals of DA neurons
Because alpha4beta2 nAChRs are the most susceptible to nicotine-induced upregulation, the data again seem consistent with the idea that selective upregulation of alpha4beta2 nAChRs underlies nicotine dependence
The upregulation of alpha4beta2* nAChRs by chronic nicotine treatment has been replicated many times in numerous systems—transfected cell lines, neurons in culture, brain slices, and smokers’ brains (Albuquerque et al., 2009; Fu et al., 2009; Lester et al., 2009; Srinivasan et al., 2011
(3) Nicotine activates alpha4beta2 nAChRs ~400-fold more effectively than it activates muscle-type nAChRs, because of cation-π and H-bond interactions at the agonist binding site (Xiu et al., 2009)
While chronic nicotine does not change the abundance or function of alpha4* nAChRs in the somata of substantia nigra pars compacta dopaminergic neurons, it does suppress baseline firing rates of these DA neurons.
These contrasting effects on GABA and DA neurons are due to upregulated alpha4* nAChR responses in GABA neurons, at both somata and synaptic terminals
The chaperoning of nAChRs by nicotine enhances the export of alpha4beta2 nAChRs from the endoplasmic reticulum (ER), and this leads to a general increase in ER exit sites (Srinivasan et al., 2011)
In mice exposed to chronic nicotine, GABA neurons in substantia nigra pars reticulata have increased baseline firing rates, both in brain slices and in anesthetized animals
ADNFLE patients who use a nicotine patch or tobacco have fewer seizures (Willoughby et al., 2003; Brodtkorb and Picard, 2006)
Variants in the gene for phosphatidylethanolamine methyl transferase, which synthesizes phosphatidylcholine and thus provides a source of choline, are also associated with choline deficiency and with schizophrenia
3-(2,4 dimethoxy)-benzylidene-anabaseine, derived from an alkaloid produced by nemertine worms, is a partial agonist at alpha7 nAChRs
It improves sensory inhibition in schizophrenics and also moderately improves their neuropsychological deficits in attention (Olincy et al., 2006)
Clinical ratings of their negative symptoms, particularly anhedonia (absence of a sense of pleasure) and alogia (poverty of content in their speech), also improve during treatment
In rodents and humans, the hippocampus is importantly implicated in cognitive sensitization, and alpha4beta2* nAChRs play key roles (Levin et al., 2006; Davis and Gould, 2009)
In the midbrain, both DA neurons (in substantia nigra pars compacta and ventral tegmental area [VTA]) and GABAergic neurons (in substantia nigra pars reticulata and VTA) express high levels of alpha4beta2* nAChRs on their somata, but only GABAergic neurons display somatic upregulation (Nashmi et al., 2007; Xiao et al., 2009)
One important role for alpha7 nAChRs, in conjunction with alpha3-containing nAChRs, is the induction of the KCC2 chloride transporter in pyramidal neurons (Liu et al., 2006)
A specific role of alpha7 nAChRs was demonstrated by failure of the induction of KCC2 by treatment with alpha7 nAChR antagonists and in a7 KO mice (Zhang and Berg, 2007)
alpha7 nAChRs are involved in the macrophage and placental cytokine response, which may be an additional role for genetic variants in these receptors in the pathogenesis of schizophrenia (Wang et al., 2003)
First, postmortem studies of the hippocampus and thalamus show diminished labeling of putative inhibitory neurons by alpha-bungarotoxin, an antagonist of alpha7 nAChRs (Court et al., 1999)
alpha7 nAChRs on inhibitory interneurons throughout the hippocampus and presynaptic alpha7 nAChRs on mossy fiber terminals in the dentate gyrus participate in the control of sensory response in the hippocampus (Gray et al., 1996; Alkondon et al., 1999
Nicotinic activation of inhibitory interneurons increases their activity and activates nitric oxide synthetase
Although alpha7 nAChRs have both presynaptic and postsynaptic expression (Frazier et al., 1998), their postsynaptic expression in humans is especially marked on inhibitory neurons of the hippocampus (Alkondon et al., 2000)
Polymorphisms in the alpha7 5' promoter and in a nearby partial duplication of the gene, FAM7A, are associated with both schizophrenia and the defect in inhibition (Leonard et al., 2002)
Thus, the brainstem can regulate hippocampal response in the presence of high sensory input.
The ‘‘volume transmission’’ hypothesis states that ACh released from presynaptic terminals spreads to more distant areas, reaching concentrations < 1 mM (Descarries et al., 1997), but that multiple presynaptic impulses produce enough summed release to activate receptors (Lester, 2004)
The neurodevelopmental program depends in part on alpha7 signaling (Liu et al.,2006)
Three lines of evidence support the possibility that the failure of sensory inhibition in schizophrenia results from decreased expression of alpha7 nAChRs
Yet some of the other genes identified, such as NRG1, are involved in the assembly of alpha7 nAChRs, further supporting a potential link between alpha7 nAChRs and schizophrenia (Mathew et al., 2007)
Because excess activation of nAChRs damages neuronal health and brain function, organisms have a clear need to restrict the degree of nAChR activation
Nicotinic receptor control over GABAergic neuronal development and mature activity may represent a point of convergence for diseases such as schizophrenia (see next section), some amblyopias (Bavelier et al., 2010), and some epilepsies (Klaassen et al., 2006), which distort the excitatory-inhibitory balance in general and implicate GABAergic signaling defects in particular
Neuronal maturation and loss of synaptic lability appear to be correlated with the onset of lynx1 expression
In 2011, we know that cholinergic actions in the brain govern various processes: cognition (attention and executive function) (Couey et al., 2007; Levin and Rezvani, 2007; Heath and Picciotto, 2009; Howe et al., 2010), learning and memory (Gould, 2006; Couey et al., 2007; Levin and Rezvani, 2007), mood (anxiety, depression) (Picciotto et al., 2008), reward (addiction, craving) (Tang and Dani, 2009), and sensory processing (Heath and Picciotto, 2009)
While genetic linkages of lynx family members to neurological disorders have not been found, evidence for cholinergic dysregulation has been linked to a lynx family member expressed in nonneuronal tissues and involved in human disease (Chimienti et al., 2003), and as such, alterations in lynx dosage may be useful in ameliorating cognitive decline associated with neuropsychiatric disorders.
Single-nucleotide polymorphisms found in the human alpha5, alpha3, beta4 gene cluster are associated with nicotine dependence and its age-dependent onset; number of cigarettes smoked per day and ‘‘pleasurable buzz’’ elicited by smoking; alcoholism, sensitivity to the depressant effects of alcohol, and age of alcohol initiation; cocaine dependence; opioid dependence; lung cancer; and cognitive flexibility (Erlich et al., 2010; Hansen et al., 2010; Improgo et al., 2010; Saccone et al., 2010; Zhang et al., 2010)
Each lynx paralog has a relative binding specificity and modulatory capability on alpha4beta2 (Miwa et al., 1999; Iban˜ ez-Tallon et al., 2002; Levitin et al., 2008), alpha3 (Arredondo et al., 2006), and alpha7 (Chimienti et al., 2003; Levitin et al., 2008; Hruska et al., 2009) nAChR subtypes; some interactions actually enhance nicotinic responses (Chimienti et al., 2003; Levitin et al., 2008), or their Ca2+ components (Darvas et al., 2009)
Therefore, the evolutionary relationship between lynx modulators and the alpha-neurotoxins agrees with the view that lynx modulators govern critical control points in the pathway of nicotinic receptor signaling
Lynx1, the first discovered member of this family expressed in the brain (Miwa et al., 1999), has an overall inhibitory effect on nAChR function
Removal of the molecular brake provided by lynx proteins can lead to nicotinic receptor hypersensitivity—larger direct nicotinic responses, slowed desensitization kinetics (Miwa et al., 2006), and enhanced sensitivity of the EPSC frequency in the cortex to nicotine (Tekinay et al., 2009)
This indicates that lynx proteins exist, genetically, as upstream modulators of nicotinic receptor function and cholinergic signaling and can exert control over cholinergic-dependent processes
Indeed, cholinergic enhancement (via cholinesterase inhibition) reopens the critical period for visual acuity in adult wild-type mice (Morishita et al., 2010), indicating that cellular mechanisms for robust plasticity are maintained in adulthood through the cholinergic system but are suppressed by the action of lynx.
Lynx1 upregulation during a critical neurodevelopmental period, the switch in the sign of GABAergic signaling, and coexpression of lynx with GABAergic subsets all indicate a possible role of lynx mediating the timing of such developmental transitions
Most brain HS nAChRs reside on presynaptic terminals, where they stimulate neurotransmitter release (Gotti et al., 2006; Albuquerque et al., 2009)
As GPI-anchored proteins can bind to transmembrane receptors intracellularly, the interactions of lynx with nAChRs could potentially alter receptor trafficking, stoichiometry, and surface number (Lester et al., 2009)
Abolishing receptor function through null mutations or pharmacological blockers of nAChRs abolished some of the gain-offunction phenotypes in lynx mouse models, indicating that nAChRs are necessary for the expression of lynx perturbations (Miwa et al., 2006)
Developmental changes in nAChR functions may play a role in nicotine addiction, as a central question in tobacco control is young adult smokers’ marked sensitivity to developing nicotine dependence (DSM-V Nicotine Workgroup, 2010; DiFranza et al., 2000; Difranza, 2010)
Recent studies provide evidence both that nicotinic signaling partially underlies these schizophrenia-related inhibitory defects and that nicotinic drugs have possible therapeutic roles
Finally, nAChRs exist in complexes in the brain; interacting proteins engage in complexes with nAChRs and aid in the assembly and trafficking of nAChR to the plasma membrane; examples are RIC-3 (Lansdell et al., 2005), 14-3-3 proteins (Jeanclos et al., 2001), neurexins (Cheng et al., 2009), and VILIP-1 (Lin et al., 2002)
Proteins that engage nAChRs within stable complexes, such as lynx family members, provide a homeostatic influence over nicotinic receptor systems
In an alpha4beta2* nAChR-expressing cell, coexpression of lynx1 results in reduced agonist sensitivity, accelerated onset of desensitization, and slower recovery from desensitization (Ibanez-Tallon et al., 2002)
In most regions that receive cholinergic innervation, the high density of acetylcholinesterase (which can hydrolyze ACh at a rate of one per 100 ms!) might vitiate the volume transmission mechanism
Mutations in nicotinic receptor subunits are linked to human disease, alpha4 and beta2 in some epilepsies, alpha7 in schizophrenia, and alpha5 in nicotine addiction; and each mutation ultimately manifests itself as an imbalance in the properties of neuronal circuits
Autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) is caused by missense mutations in either the alpha4 or the beta2 subunit
For instance, early expression of lynx1 family member, PSCA, prevents programmed cell death of parasympathetic neurons (Hruska et al., 2009)
This transporter lowers the internal Cl- concentration of the neuron and changes GABA from a depolarizing to a hyperpolarizing or inhibitory neurotransmitter
As a consequence of nAChR hypersensitivity, lynx1 knockout mice display increased levels of Ca2+ in neurons, enhancements in synaptic efficacy, and improved learning and memory functions (Miwa et al., 2006; Darvas et al., 2009; Tekinay et al., 2009)
For instance, adult lynx1KO mice display heightened ocular dominance plasticity after the normal close of the critical period (Morishita et al., 2010)
These findings indicate that suppression of the cholinergic system by lynx proteins stabilizes neural circuitry
Third, persons with schizophrenia have the greatest rate and intensity of cigarette smoking of any identifiable subgroup in the population
However, when all genetic factors are eliminated by studying monozygotic twins who are discordant for both tobacco use and Parkinson’s disease, tobacco smoking and chewing still decrease the risk of Parkinson’s disease (Tanner et al., 2002; Wirdefeldt et al., 2005)
In many persons with schizophrenia, cerebral evoked potential recording shows diminished inhibition of the response to repeated stimuli (Adler et al., 1982) (Figure 2A), and animal models of this phenomenon point to a defect in hippocampal inhibition
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