Nicotinic Receptors in Brain Diseases 765 variant allele of Chrna7 has been identified in mice. This allele is linked to vari- ability in α7 expression in the hippocampus (Stitzel et al., 1996), neuroanatomical distribution of α7 nAChRs in the hippocampus (Adams et al., 2001), developmental expression of α7 nAChRs in the hippocampus (Adams et al., 2006), and audi- tory gating deficits (Stevens et al., 2001). The fact that the allele of Chrna7 that leads to reduced α7 expression in the hippocampus also leads to impaired auditory gating is consistent with the role of Chrna7 in regulating the auditory gating phe- notype in schizophrenics. Recently, Liu et al. (2006) reported that α7nAChRsare involved in the normal development of the GABAergic system in the hippocam- pus. Thus, abnormal expression of α7 nAChRs during pre- and perinatal periods of development may have long-term consequences on brain function. Suggestive support for a developmental role of α7 nAChRs in impaired auditory gating comes from two recent studies that have shown that perinatal dietary supplementation with choline, an α7-selective agonist, permanently improves gating in two animal models of impaired auditory gating (Stevens et al., 2008a,b). 3.2 Autism A second disease where there appears to be altered expression of nAChRs is autism. Studies have shown that high-affinity nicotinic receptors as measured by [3H] epi- batidine, α4 RNA and anti-α4 antibodies, are reduced in various cortical regions in autistic subjects (Martin-Ruiz et al., 2004; Perry et al., 2001). Using both [3H] epi- batidine and anti-α4 antibodies, Lee et al. (2002) and Martin-Ruiz et al. (2004)also reported that α4 nAChRs are reduced in cerebellar regions in subjects with autism relative to normal controls. The α7 subunit was not found to be altered in expression in cortical regions of autistic patients but was found to be upregulated in cerebellum (Lee et al., 2002; Martin-Ruiz et al., 2004); the binding of [125I] α-bungarotoxin was increased in cerebellum although no change in α7RNAorα7 immunoreactiv- ity was detected. Finally, in a small sample, α7 and β2 but not α4 immunoreactivity was found to be decreased in the thalamus of individuals with autism (Ray et al., 2005). In addition to altered levels of nAChRs, there also appear to be increased num- bers and enlarged morphology of cholinergic neurons in the cortex of children with autism (Bauman and Kemper, 2005). Based on this observation, it has been hypothesized that the downregulation of nAChRs in the cortex and thalamus in autism is the result of a homeostatic response to hypercholinergic activity in the cortex (Lippiello, 2006). The potential hyperactivity in the cortex of individuals with autism may explain the low level of smoking associated with autism relative to both the general population and other mental diseases (Bejerot and Nylander, 2003; Poirier et al., 2002). Nonetheless, there currently are no pharmacological or animal model data to convincingly implicate nAChRs in the etiology of autism. Therefore, the relevance of the altered expression of nAChRs in this disease remains to be determined. 766 J.A. Stitzel 4 Genetic Variants of nAChR Subunit Genes and Brain Disease Each nAChR subunit is encoded by a different gene and any mutation in any of these genes that affects the expression or function of an nAChR could lead to disease or contribute to individual differences in risk for disease. In this section, one dis- ease directly caused by mutations in nAChR subunit genes is discussed. In addition, the potential role of genetic variability in nAChR subunit genes in altering risk for disease is summarized. 4.1 Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE) Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is the only brain disease known to be caused by mutations in genes that code for nicotinic receptor subunits. ADNFLE is a rare, inherited form of epilepsy characterized by hyperki- netic or tonic seizures that tend to occur in clusters. Seizures also are of frontal lobe origin and tend to occur during periods of light sleep (Scheffer et al., 1995). To date, there have been ten mutations in genes that code for nAChR subunits that cause ADNFLE, four in CHRNA4 the gene that encodes the nAChR α4 subunit (Hirose et al., 1999; Leniger et al., 2003; McLellan et al., 2003; Phillips et al., 2000; Saenz et al., 1999; Steinlein et al., 1995, 1997, 2000), five in CHRNB2, the gene that codes the β2 nAChR subunit (Bertrand et al., 2005; De Fusco et al., 2000; Hoda et al., 2008; Phillips et al., 2001), and one in CHRNA2, the gene that encodes the α2 nAChR subunit (Aridon et al., 2006). For more details on these ADNFLE-causing mutations, please see the recent review by Steinlein and Bertrand (2008). A fifth mutation in CHRNA4 recently has been identified that may add to this long list of nAChR subunit gene mutations that cause ADNFLE (Chen et al., 2009b). There also is some debate as to whether the seizure disorder caused by the CHRNA2 mutation is ADNFLE or a related seizure disorder (Hoda et al., 2009). Regardless of whether the seizure disorder caused by the CHRNA2 mutation is ADNFLE or a related dis- ease, it still is an example of a mutation in an nAChR subunit gene that directly causes an inherited disease. Although mutations in CHRNA2, CHRNA4, and CHRNB2 have been shown t o cause ADNFLE or related seizure disorders, how these mutations cause epilepsy remains unknown. However, in vitro functional analysis indicates that a common feature of nAChRs possessing ADNFLE mutations is a gain of function, either by increased sensitivity to acetylcholine or reduced desensitization (Aridon et al., 2006; Bertrand et al., 2002; Hoda et al., 2008, 2009; Leniger et al., 2003; Moulard et al., 2001; Phillips et al., 2001). In addition, two recent studies found that smoking or nicotine treatment decreased seizure frequency in ADNFLE patients with nAChR mutations (Brodtkorb and Picard, 2006; Willoughby et al., 2003). The therapeutic effect of smoking/nicotine presumably was the result of decreasing or inhibiting the function of the hyperactive nAChRs via the well-characterized desensitizing effect of nicotine on α4β2 ∗ . A mechanism by which nAChR gain of function mutations Nicotinic Receptors in Brain Diseases 767 might lead to ADNFLE has been suggested by studies using two lines of mice a engineered to possess different ADNFLE mutations in Chrna4 (Klaassen et al., 2006). In these studies, it was found that nicotine was greater than 20 times more potent at activating inhibitory postsynaptic currents in cortical regions of mice with ADNFLE mutations than in their control littermates. In contrast, nicotine had no effect on excitatory postsynaptic currents. Based on these data and the observation that picrotoxin, a use-dependent GABA antagonist, transiently eliminated epilep- tiform activity in ADNFLE mice, the authors concluded that nAChR-mediated ADNFLE may be caused by hyperactive nAChRs in GABAergic neurons that leads to synchronization of cortical networks. An interesting feature of ADNFLE-causing nAChR mutants is their differen- tial sensitivity to the antiepileptic drug carbamazepine. Carbamazepine can inhibit nAChR function via open channel blockade and three of the known ADNFLE mutations, two in α4 and one in β2, have substantially increased sensitivity to inhi- bition by carbamazepine (Bertrand et al., 2005; Hogg and Bertrand, 2004; Picard et al., 1999). For individuals with any of these carbamazepine-sensitive mutations, carbamazepine has proven to be an effective treatment. In contrast, other ADNFLE- causing mutations in CHRNA4 and CHRNA2 either do not show altered sensitivity to carbamazepine or actually show a reduced sensitivity to inhibition by this drug (Bertrand et al., 2005; Hoda et al., 2009; Leniger et al., 2003). Individuals with these mutations apparently do not benefit from carbamazepine treatment. Thus knowing which nAChR mutation a patient carries can be a valuable aid in treatment selec- tion. However, it should be pointed out that mutations in nAChR subunit genes only account for a fraction of total ADNFLE cases and therefore, the predictive power of nAChR subunit gene mutation identification is restricted to a small percentage of ADNFLE patients. 4.2 Other Genetic Variants in nAChR Subunit Genes and Their Relation to Diseases of the Brain A significant number of polymorphisms and rare mutations in nAChR subunit genes have been implicated in various diseases of the brain through linkage and association studies. Diseases thought to be influenced by nAChR subunit gene vari- ants include schizophrenia, Alzheimer’s disease, non-ADNFLE epilepsies, various cognitive disorders including attention deficits, and drug addiction-related pheno- types. Because there have been several recent reviews on this topic (Portugal and Gould, 2008; Steinlein and Bertrand, 2008; Stitzel, 2008) it is not extensively reviewed here. However, at the time of these reviews, studies began appearing that implicated the gene cluster on chromosome 15q24 that contains CHRNA5, CHRNA3, and CHRNB4 in various aspects of addiction to nicotine, alcohol, and cocaine. This cluster of genes encodes the α5, α3, and β4 nAChR sub- units, respectively. Because this gene cluster repeatedly has been implicated in influencing individual variability in addiction-related measures over the past two years, it warrants some further discussion. The first two reports that implicated this nAChR gene cluster in addiction were published by Bierut et al. (2007) and 768 J.A. Stitzel Saccone et al. (2007). These two studies identified single nucleotide polymor- phisms (SNPs) in both CHRNA5 and CHRNA3 that were associated with nicotine dependence. Subsequent studies have confirmed the association between the CHRNA5 and CHRNA3 SNPs and nicotine dependence (Baker et al., 2009; Bierut et al., 2008; Caporaso et al., 2009; Chen et al., 2009a; Saccone et al., 2009; Spitz et al., 2008; Stevens et al., 2008; Thorgeirsson et al., 2008; Wang et al., 2009; Weiss et al., 2008) as well as implicated the gene cluster in individual differences in level of smok- ing (Berrettini et al., 2008; Le et al., 2008), subjective effects of smoking (Sherva et al., 2008), age of initiation of smoking (Schlaepfer et al., 2008), cocaine addic- tion (Grucza et al., 2008), and alcohol dependence (Joslyn et al., 2008; Schlaepfer et al., 2008; Wang et al., 2008). The same SNPS also have been associated with risk for lung cancer (Amos et al., 2008; Hung et al., 2008; Liu et al., 2008; Shiraishi et al., 2009; Spitz et al., 2008; Thorgeirsson et al., 2008) and chronic obstructive pulmonary disease (COPD) (Pillai et al., 2009; Young et al., 2008). Whether the association between the CHRNA5-CHRNA3 SNPs and lung cancer or COPD are due to an altered risk for smoking or represent an independent signal remains a matter of debate (Volkow et al., 2008). Although beyond the scope of this review (see Egleton et al. (2008), and Song and Spindel (2008) for recent reviews of this topic), nAChRs, including those that contain the α3 and/or α5 subunit are expressed in pulmonary epithelial cells and lung cancer cells so an independent role of SNPs in CHRNA3 and/or CHRNA5 on risk for these diseases certainly is feasible. Although the repeated associations between the CHRNA5–CHRNA3–CHRNB4 gene cluster and the mentioned addiction-related measures strongly suggest that there is one or more polymorphism in the cluster that alters risk for drug use and abuse, the identity of the causative SNP or SNPs is not known. However, a strong candidate is an amino-acid-altering SNP in CHRNA5 that changes a highly conserved aspartic acid codon at amino acid position 398 in the α5 s ub- unit to an asparagine codon. Preliminary in vitro data indicate that the amino acid change associated with increased risk for nicotine dependence (asparagine at position 398) reduces the function of α4β2α5 nAChRs (Bierut et al., 2008). Whether this functional effect of the polymorphism is responsible for altered lia- bility to nicotine dependence and if so, by what mechanism does the change in function of α4β2α5 nAChRs alter addiction risk, are questions that remain to be answered. 5 Diseases Where nAChRs Are Implicated by Therapeutic Effects of Nicotine A putative role for nAChRs in schizophrenia was suggested by the high rate of smoking in schizophrenic patients and the observation that nicotine normalizes neu- rophysiological deficits associated with the disease. As described elsewhere in this review, subsequent studies provided strong evidence for a role of nAChRs in the Nicotinic Receptors in Brain Diseases 769 etiology of this disease. However, there are some diseases where nicotine has been shown to have therapeutic value although a specific role of nAChRs has yet to be established. Two examples of such diseases are discussed here. 5.1 Tourette Syndrome Tourette syndrome is a neurological disorder characterized by repetitive, stereo- typed, involuntary movements and vocalizations called tics (NINDS, 2008). In cases where the tics interfere with normal functioning, therapeutics such as haloperidol often are used. The first evidence for the role of nicotinic receptors in Tourette syndrome came from a study by Sanberg et al. (1988) that reported that nicotine gum in combination with haloperidol improved symptoms in two patients where haloperidol alone was without effect. Follow-up studies have confirmed that nico- tine gum potentiates the therapeutic effects of haloperidol in Tourette syndrome (McConville et al., 1991, 1992; Sanberg et al., 1989). In addition, the use of a trans- dermal nicotine patch rather than nicotine gum has been shown to have long-lasting potentiation of the effects of neuroleptics on tic frequency and severity (Dursun et al., 1994; Silver et al., 1996, 2001). Dursun et al. (1994) also r eported that nico- tine alone improved Tourette syndrome symptoms. In studies where it has been assessed, combined nicotine/neuroleptic treatment also improved measures of atten- tion in Tourette syndrome patients relative to neuroleptic treatment alone (Dursun et al., 1994; Howson et al., 2004). Although the mechanism through which nico- tine improves symptoms of Tourette syndrome is not known, a relatively recent study demonstrated that nicotine normalized deficits in inhibitory function of motor cortex in Tourette syndrome patients ( Orth et al., 2005). Nonetheless, there are no pharmacological data to suggest which nAChR subtypes might be responsible for the therapeutic effects of nicotine in this disease and no postmortem data to eval- uate whether there might be abnormalities in nAChR expression that may directly contribute to the disease. 5.2 Down Syndrome Down syndrome is a genetic disease caused by the inheritance of an extra copy (tri- somy) of chromosome 21. In addition to some common physical features and health problems, most subjects with Down syndrome also have mild to moderate mental retardation. Postmortem brain tissue of Down syndrome patients exhibits amyloid plaques (Burger and Vogel, 1973; Ellis et al., 1974) and cholinergic deficits (Yates et al., 1980) similar to those observed in postmortem brain tissue from Alzheimer patients. In addition, studies with primary cultures from Down syndrome patient brain or cell lines derived from a mouse model of Down syndrome (trisomy 16) suggest that there are cholinergic deficiencies in trisomy 21/16 neurons (Allen et al., 2000; Cardenas et al., 2002; Fiedler et al., 1994). Based on the apparent cholinergic deficits in Down syndrome, Lubec and colleagues (Bernert et al., 2001; Seidl et al., 770 J.A. Stitzel 2000) examined whether transdermal nicotine could improve some of the cognitive deficits associated with Down Syndrome. In both published studies, nicotine was found to improve cognitive performance in the Down syndrome subjects. However, despite the cholinergic deficits and presumably related therapeutic effect of nicotine in Down syndrome, a specific contribution of nAChRs remains to be established for this disease. For example, neither Lee et al. (2002) nor Ray et al. (2005) found any deficits in [3H] epibatidine or [125I] α bungarotoxin binding in postmortem brain of Down syndrome patients. These findings contradict the observation by Engidawork et al. (2001) that the expression of α3 and α7 subunits is altered in Down syndrome. This apparent discrepancy likely is due to the fact that Engidawork et al. (2001)used immunohistochemical methods to detect nAChR subunits. The use of antibodies for standard immunohistochemical detection of nAChR subunits has come under recent scrutiny (Jones and Wonnacott, 2005; Moser et al., 2007). Another mechanism proposed for the therapeutic effect of nicotine in Down syndrome is that the high levels of β amyloid present in the Down syndrome brain are inhibiting the function of α7 nAChRs essentially as described above in Alzheimer’s disease (Deutsch et al., 2003). However, a recent report found no cor- relation between β amyloid levels and dementia in older Down syndrome subjects (Jones et al., 2009). Therefore, despite the therapeutic effect of nicotine in Down syndrome, the specific role of nAChRs remains elusive. 6 Conclusions The research summarized in this review suggests that nAChRs contribute to a wide range of neuropathologies. In many cases the combined therapeutic effect of nico- tine and/or nicotinic drug in addition to detectable differences in nAChR expression provides compelling evidence for a contribution of nAChRs to neuropathology. However, in the diseases that fall into this category, including Alzheimer’s and Parkinson’s disease, schizophrenia, and autism ( among others), the mechanism responsible for the altered expression of the nAChRs is not known. Moreover, whether the altered expression of nAChRs and these diseases is causal or casual remains to be established. In the case of ADNFLE, identified mutations in nAChR subunit genes clearly define a role of nAChRs in diseases of the brain and ani- mal models provide a plausible mechanism. In contrast, the contribution of genetic variants in genes that code for nAChR subunits in diseases other than ADNFLE is only beginning to emerge. Not surprisingly, very little is known regarding the biological mechanisms responsible for the associations between nAChR subunit gene variation and diseases such as nicotine dependence. Finally, there are several diseases such as Tourette syndrome and Down syndrome where nicotine has ther- apeutic effects despite the lack of any detectable alterations in nAChR expression or function. In summary, there is substantial evidence that nAChRs contribute to a wide assortment of brain disease. Nonetheless, much work remains to be done to establish the mechanisms through which nAChRs contribute to the etiology of disease. Nicotinic Receptors in Brain Diseases 771 Acknowedgments This work was supported by grants from the NIH (CA089392, DA022462, MH068582). 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Perry EK (2000) Nicotine binding in human striatum: elevation in schizophrenia and reductions in dementia with Lewy bodies, Parkinson’s disease and Alzheimer’s disease and in relation to neuroleptic medication in nAChR expression provides compelling evidence for a contribution of nAChRs to neuropathology. However, in the diseases that fall into this category, including Alzheimer’s and Parkinson’s disease, . assortment of brain disease. Nonetheless, much work remains to be done to establish the mechanisms through which nAChRs contribute to the etiology of disease. Nicotinic Receptors in Brain Diseases 771 Acknowedgments