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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