Genetics of AD and PD 755
Zhou W, Freed CR (2005) DJ-1 up-regulates glutathione synthesis during oxidative stress and
inhibits A53T alpha-synuclein toxicity. J Biol Chem 280:43150–43158
Zhou W, Zhu M, Wilson MA, Petsko GA, Fink AL (2006) The oxidation state of DJ-1 regulates
its chaperone activity toward alpha-synuclein. J Mol Biol 356:1036–1048
Ziegler SG, Eblan MJ, Gutti U, Hruska KS, Stubblefield BK, Goker-Alpan O, LaMarca ME,
Sidransky E (2007) Glucocerebrosidase mutations in Chinese subjects from Taiwan with
sporadic Parkinson disease. Mol Genet Metab 91:195–200
Zimprich A, Muller-Myhsok B, Farrer M, Leitner P, Sharma M, Hulihan M, Lockhart P,
Strongosky A, Kachergus J, Calne DB, Stoessl J, Uitti RJ, Pfeiffer RF, Trenkwalder C, Homann
N, Ott E, Wenzel K, Asmus F, Hardy J, Wszolek Z, Gasser T (2004) The PARK8 locus
in autosomal dominant parkinsonism: confirmation of linkage and further delineation of the
disease-containing interval. Am J Hum Genet 74:11–19

Nicotinic Receptors in Brain Diseases
Jerry A. Stitzel
Abstract The existence of neuronal nicotinic acetylcholine receptor (nAChRs)
expression in the brain was discovered 30 years ago. Although the relevance of
neuronal nAChRs at the time of their discovery was debated, it is now clear that
nAChRs are expressed throughout the brain where they mainly serve a modulatory
role. Neuronal nAChRs increasingly have become of interest due to the many obser-
vations that various nAChR subtypes exhibit abnormal expression or function in a
wide assortment of neurological diseases. In this review, the putative role of nAChRs
in brain disease is discussed in several broad categories: (1) diseases associated with
a loss of nAChRs, (2) diseases associated with innate differences in the expression
of nAChRs, (3) diseases associated with genetic variability in genes that code for
nAChR subunit proteins, and (4) diseases in which nAChRs are implicated based on
the observation that nicotine has a therapeutic effect.
Keywords Receptors, nicotinic · Parkinson’s disease · Alzheimer’s dis-
ease · Schizophrenia · Autism · Autosomal dominant nocturnal frontal lobe
epilepsy (ADNFLE) · CHRNA5 · CHRNA3 · Nicotine dependence · Tourette’s

syndrome · Down syndrome
Contents
1 Introduction 758
1.1 Brief History
758
1.2 Activation, Desensitization, and Upregulation
759
2 Diseases Associated with Loss of Brain Nicotinic Receptors
760
2.1 Parkinson’s Disease
760
2.2 Alzheimer’s Disease
761
3 Diseases Associated with Innate Differences in the Expression of nAChRs
763
J.A. Stitzel (B)
Department of Integrative Physiology, Institute for Behavioral Genetics, University of Colorado,
Boulder, CO 80309, USA
e-mail:
757
J.P. Blass (ed.), Neurochemical Mechanisms in Disease,
Advances in Neurobiology 1, DOI 10.1007/978-1-4419-7104-3_22,
C

Springer Science+Business Media, LLC 2011
758 J.A. Stitzel
3.1 Schizophrenia
763
3.2 Autism
765

4 Genetic Variants of nAChR Subunit Genes and Brain Disease
766
4.1 Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE)
766
4.2 Other Genetic Variants in nAChR Subunit Genes
and Their Relation to Diseases of the Brain
767
5 Diseases Where nAChRs Are Implicated by Therapeutic Effects of Nicotine
768
5.1 Tourette Syndrome
769
5.2 Down Syndrome
769
6 Conclusions
770
References
771
1 Introduction
1.1 Brief History
Neuronal nicotinic acetylcholine receptors (nAChRs) are members of the cys-
teine loop superfamily of ligand gated ion channels that includes ionotropic 5-HT,
GABA, and glycine receptors. As their name implies, nAChRs are receptors for the
endogenous neurotransmitter acetylcholine in the nicotinic branch of the choliner-
gic system. The existence of nAChR in the brain was first demonstrated by ligand
binding studies in the 1980s. Using radio-ligand binding techniques, several groups
established that there were at least two distinct nAChR populations in the rodent
brain: one that binds the ligand [125I]-α-bungarotoxin with high affinity (Marks
and Collins, 1982; Morley et al., 1979; Oswald and Freeman, 1981) and one that
binds the ligands [3H]-L-nicotine or [3H] acetylcholine with high affinity (Abood
et al., 1980; Marks and Collins, 1982; Romano and Goldstein, 1980; Schwartz et al.,

1982; Sershen et al., 1981). The two binding sites also were found to be expressed in
overlapping yet distinct patterns in the brain (Clarke et al., 1985; Marks et al., 1986;
Marks and Collins, 1982). At the time of their identification, the functional relevance
of these binding sites in the brain was not clear (Abood et al., 1980, 1981; Sershen
et al., 1981). However, from the mid-1980s through the early 1990s cDNAs for mul-
tiple nAChR subunits were cloned from rat and chicken brain (Boyd, 1997). These
studies not only led to the identification of 11 different genes (12 in chickens) that
code for neuronal nAChR subunits but also demonstrated that various subunit com-
binations could form functional nAChRs that could be activated by acetylcholine
and nicotine. The subunit genes identified were named α2–α10 (α8 only found in
chickens) and β2–β4 based on the presence (α subunit) or absence (β subunit) of
vicinal cysteines in the N-terminal extracellular domain and the order in which they
were cloned. Neuronal nAChRs, like nAChRs at the neuromuscular junction, also
were found to be composed of five subunits that form a pentameric ring around a
central cation pore. These early studies also demonstrated that some nAChRs are
heteromeric, requiring both an α subunit (α2–α4, α6) and a β subunit (β2orβ4) in
order to form a functional receptor in vitro. The most abundant heteromeric nAChR
Nicotinic Receptors in Brain Diseases 759
in brain i s comprised of the subunits α4 and β2 (Flores et al., 1992; Whiting et al.,
1991). The α4β2
∗
(the asterisk indicates that other subunits such as α5 can contribute
to α4β2 nAChRs) receptor exhibits high affinity for nicotinic agonists and has been
demonstrated to be the [3H]-L nicotine binding site described in the early ligand-
binding studies (Flores et al., 1992; Marubio et al., 1999; Picciotto et al., 1995;
Whiting et al., 1991). Other nAChR α subunits were identified that could form func-
tional pentameric receptors in vitro without a β subunit. The most prevalent of these
so-called homomeric nAChRs in the brain is composed of α7 subunits. Homomeric
α7 nAChRs exhibit low affinity for nicotinic agonists and immunological (Chen
and Patrick, 1997) and genetic studies (Orr-Urtreger et al., 1997) demonstrated

that α7 nAChRs are the previously described [125I]-α-bungarotoxin binding sites in
brain.
Although α4β2
∗
nAChRs are the most abundant nAChR expressed in the brain,
several other heteromeric nAChR subtypes exist in the brain. For example, within
dopamine terminals there are at least five different heteromeric nAChRs composed
of anywhere between two and four different subunits (Champtiaux et al., 2002;
Cui et al., 2003; Klink et al., 2001; Marubio et al., 2003; Salminen et al., 2004).
The nAChRs on dopamine terminals in the striatum include α4β2, α4β2α5, α6β2,
α6β2β3, and α4α6β2β3. Data also indicate that the nAChRs in GABAergic ter-
minals are α4β2 and α4β2α5 (Lu et al., 1998; McClure-Begley et al., 2009;Zhu
and Chiappinelli, 1999), whereas nAChRs that modulate acetylcholine release in
the interpeduncular nucleus are α3β4 and α3β3β4 heteromers (Grady et al., 2001,
2009). A combination of immunoprecipitation experiments and in situ hybridization
studies also suggest the existence of additional heteromeric nAChR subtypes (Gotti
et al., 2006b), including an α7β2
∗
subtype (Liu et al., 2009) although the functional
relevance of these potential nAChR subtypes remains to be determined.
1.2 Activation, Desensitization, and Upregulation
Activation of nAChRs by agonists leads to the opening of a central channel that
is permeable to cations including calcium (Mulle et al., 1992). Permeability to cal-
cium is receptor subtype-dependent with α7 nAChRs exhibiting the greatest calcium
permeability (Fucile et al., 2003; Fucile, 2004; Ragozzino et al., 1998). Although
acute exposure to a nicotinic agonist activates nAChRs, continuous exposure to
activating and even subactivating concentrations of agonist leads to receptor desen-
sitization, a state in which the receptors become refractory to activation to agonists
(Giniatullin et al., 2005; Quick and Lester, 2002). This property of nAChRs also
is subtype-dependent with α7 nAChRs exhibiting the fastest rate of desensitization

(Couturier et al., 1990; Seguela et al., 1993). However, due to the low sensitivity
of α7 nAChRs to activation by nicotinic agonists, α7 nAChRs appear to remain
active at nicotine concentrations in the range found in smokers (Mansvelder et al.,
2002; Wooltorton et al., 2003). In contrast, α4β2
∗
nAChRs appear to be desensi-
tized at the same concentrations of nicotine (Mansvelder et al., 2002; Mansvelder
and McGehee, 2000). The ability of nicotine to produce long-term desensitization
760 J.A. Stitzel
of at least some nAChR subtypes at physiologically relevant concentrations have
led some to refer to nicotine as a time-averaged antagonist (Hulihan-Giblin et al.,
1990).
Another property of at least some nAChR subtypes is upregulation of receptor
numbers in response to long-term nicotine exposure. This phenomenon first was
discovered in rodents by Marks et al. (1983) and Schwartz and Kellar (1983). Both
of these groups demonstrated that chronic treatment of mice and rats led to upreg-
ulation of what we now know are α4β2
∗
nAChRs. High doses of nicotine also led
to modest increases in α7 nAChRs (Marks et al., 1983). Upregulation of α4β2
∗
nAChRs also is seen in brain tissue from smokers (Benwell et al., 1988; Breese et al.,
1997; Perry et al., 1999). This upregulation of nAChRs has been termed paradoxical
because the expected effect of chronic agonist exposure is receptor downregulation
(Wonnacott, 1990). However, it has been postulated that the upregulation is due to
the time-averaged antagonist property of nicotine. Support for this possibility comes
from a study by Marks et al. (2004) that demonstrated that, despite the increase
in numbers of α4β2
∗
nAChRs following chronic nicotine treatment, the level of

function of α4β2
∗
nAChRs remained unchanged relative to controls. These findings
suggest that upregulation serves as a homeostatic mechanism to maintain normal
levels of receptor function in the presence of a “time-averaged” antagonist.
Due to the widespread expression of nAChRs throughout the brain and their
involvement in modulating the release of many neurotransmitters, it is not surprising
that aberrant expression or function of nAChRs might contribute to a wide range of
diseases. In the following sections, diseases of the brain in which nAChRs have been
implicated are discussed in four broad categories, diseases associated with the loss
of nicotinic receptors, diseases associated with innate differences in the expression
of nicotinic receptors, diseases related to genetic variants in the genes that code for
the nicotinic receptor subunits, and diseases in which nAChRs have been implicated
due to a therapeutic effect of nicotine.
2 Diseases Associated with Loss of Brain Nicotinic Receptors
The diseases associated with loss of nAChRs are typically neurodegenerative dis-
eases. The two most studied diseases that are associated with the loss of nicotinic
receptors in the brain are Parkinson’s and Alzheimer’s.
2.1 Parkinson’s Disease
In Parkinson’s disease (PD), loss of nAChRs occurs in the nigrostriatal pathway
(Aubert et al., 1992; Pimlott et al., 2004; Quik et al., 2004) as well as in the basal
forebrain and cortex (Aubert et al., 1992; Lange et al., 1993; Perry et al., 1995; Rinne
et al., 1991). Early studies indicated that high-affinity nAChRs are preferentially lost
in PD. A combination of studies in both rodent and nonhuman primate models of
PD suggests that the α6α4β2β3 nAChR is the most labile high affinity nAChR in
response to nigrostriatal damage (Kulak et al., 2002; Quik et al., 2005). The loss of
Nicotinic Receptors in Brain Diseases 761
this nAChR subtype also closely coincides with the loss of the dopamine transporter
(Bordia et al., 2007; Gotti et al., 2006a; Quik et al., 2004). α4β2
∗

nAChRs also
appear to be lost in animal models of PD but only when lesions are severe (Bordia
et al., 2007; Kulak et al., 2002; Quik et al., 2003). Similarly, α6β2
∗
appear to be lost
to a greater extent than α4β2
∗
nAChRs in several brain areas of PD patients (Bohr
et al., 2005; Bordia et al., 2007; Quik et al., 2004). In contrast, there appears to be
no loss of α7 nAChRs in striatal tissue in both animal models and humans (Guan
et al., 2002; Quik et al., 2005; Zoli et al., 2002). However, there may be a loss of α7
nAChRs in cortical regions of Parkinson’s disease patients (Banerjee et al., 2000;
Burghaus et al., 2003) although this finding is not universal (Guan et al., 2002).
It remains to be determined whether the loss of nAChRs in PD contributes to the
development of the disease or simply is a marker of the disease and α6β2
∗
nAChRs
are simply present on the neurons most sensitive to damage. Data from knock-out
mice demonstrate that the lack of any of the striatal expressed nAChR subunits does
not lead to striatal neurodegeneration. Thus, the simple loss of these nAChRs alone
is not sufficient to elicit a neurodegenerative state. Nonetheless, a role of nAChRs in
PD is supported by epidemiological evidence that clearly demonstrates that there is
an inverse relationship between smoking and the development of PD. Although the
mechanism through which smoking delays the onset of PD remains to be elucidated,
it is generally thought that nicotine acts as a neuroprotective agent via interaction
with nAChRs. The ability of nicotine to be neuroprotective in general and in animal
models of PD more specifically has been demonstrated in several in vitro and in vivo
studies (Quik et al., 2008). Whether nicotine acts as a neuroprotective agent through
activating or desensitizing nicotinic receptors is not clear. However, recent studies
with mice possessing a hyperactive form of the α4 s ubunit suggest that heightened

activity rather than loss of activity is neurodegenerative in the striatum (Labarca
et al., 2001; Schwarz et al., 2006). Based on this and the fact that nAChR knock-out
mice show no striatal neurodegeneration suggests that the neuroprotective proper-
ties of nicotine may be through desensitization/inactivation of nAChRs rather than
through activation.
2.2 Alzheimer’s Disease
2.2.1 Altered Expression of nAChRs
Loss of nAChRs also is associated with Alzheimer’s disease (AD). The most pro-
foundly affected nAChR subtype in AD is the α4β2
∗
subtype. Results from both
receptor-ligand binding assays (Nordberg et al., 1988; Nordberg and Winblad, 1986;
Perry et al., 2000; Whitehouse et al., 1986, 1988) and immunological experiments
(Burghaus et al., 2000; Gotti et al., 2006a; Guan et al., 2000; Martin-Ruiz et al.,
1999; Wevers et al., 1999) indicate that α4β2
∗
nAChRs are reduced by as much as
50% in cortical and hippocampal regions of postmortem brain tissue of AD patients.
α4β2
∗
nAChRs begin to decline in the earliest stages of AD (Marutle et al., 1999)
and several recent studies have shown a significant correlation between the degree
of loss of this nAChR subtype and cognitive deficits in early AD patients (Kadir
762 J.A. Stitzel
et al., 2006; Sabri et al., 2008). Other studies have reported a correlation between
the level of expression of cortical α4β2
∗
nAChRs and degree of cognitive deficits in
AD patients (Nordberg et al., 1995; Perry et al., 2000). However, not all studies have
observed a significant correlation between the expression levels of α4β2

∗
nAChRs
and cognitive deficits in early AD patients (Ellis et al., 2008, 2009). Nonetheless,
a putative role of α4β2
∗
nAChRs in AD-related neurodegeneration is supported by
the observation that β2 nAChR-null mutant mice exhibit elevated age-related neu-
rodegeneration in cortical brain areas and hippocampus and increased age-related
cognitive deficits (Zoli et al., 1999).
Some studies also have found alterations in the expression of other nAChR
subunits, including α3 and α7, in postmortem brain tissue of AD patients (Guan
et al., 2000; Mousavi et al., 2003; Wevers et al., 1999) and animal models (Bednar
et al., 2002; Jones et al., 2006;Mousavietal.,2004). However, these findings gen-
erally are not consistent. In the case of α7, some studies have found no change
in expression of this subunit (Gotti et al., 2006a; Martin-Ruiz et al., 1999), oth-
ers have found a decrease in expression of this subunit ( Burghaus et al., 2000;
Engidawork et al., 2001; Guan et al., 2000; Wevers et al., 1999), and a few stud-
ies have reported an increase in the expression of this nAChR subunit (Counts et al.,
2007; Hellstrom-Lindahl et al., 1999; Teaktong et al., 2003). This apparent dispar-
ity in the relationship between α7 expression and AD may be explained by a recent
study by Jones et al. (2006) in which α7 expression was assessed in a transgenic
mouse possessing a mutant form of the human amyloid precursor protein (APP)
that results in familial AD. Results of this study demonstrated that α7 expression
increases progressively to levels three- or fourfold higher than normal control brain
by 9 months of age. However, by 12 months of age the transgenic mice expressed
lowerlevelsofα7 than controls. Therefore, the relationship between α7 expression
and AD may be age and/or disease state-dependent. It is of interest to note that
despite the fact that several studies have demonstrated a reduction in α4β2
∗
and

potentially other nAChRs in AD patients, changes in RNA levels for these receptor
subunits generally have not been observed in AD patients (Mousavi et al., 2003;
Terzano et al., 1998). This observation suggests that the loss of nAChRs in AD is
mediated posttranscriptionally.
2.2.2 Interaction of nAChRs with β Amyloid
nAChRs also have been implicated in the etiology of AD via interactions with amy-
loid β (Aβ), a 39–43 amino acid polypeptide that is thought to play a critical role
in the pathogenesis of AD. Several studies have shown that Aβ
1-42
binds with high
affinity to both α4β2
∗
and α7 nAChRs. In addition, nicotinic receptors are impli-
cated in neuroprotection from Aβ toxicity by the observations that nicotine reduces
Aβ accumulation and neurotoxicity both in vitro (Kihara et al., 1998, 1999, 2001;
Liu and Zhao, 2004; Zamani et al., 1997) and in animal models (Gahring et al., 2003;
Hellstrom-Lindahl et al., 2004; Nordberg et al., 2002; Zhang et al., 2006). Moreover,
the deposition of Aβ is significantly reduced in postmortem brain from AD patients
who were smokers (Hellstrom-Lindahl et al., 2004). However, there are conflicting
Nicotinic Receptors in Brain Diseases 763
data regarding whether the interaction of Aβ with various nAChR subtypes acti-
vates (Chin et al., 2006; Dineley et al., 2001, 2002; Fu and Jhamandas, 2003)or
inhibits (Grassi et al., 2003; Lamb et al., 2005; Liu et al., 2001, 2009; Magdesian
et al., 2005; Soderman et al., 2008; Tozaki et al., 2002; Wu et al., 2004) the function
of the receptors. In addition, a recent paper reported that oligomeric Aβ
1-42
at low
concentrations (1 nM) selectively inhibits a novel and putatively α7β2nAChR(Liu
et al., 2009). It also has been reported that there is a physical interaction between
Aβ and α7 nAChRs (Wang et al., 2000a,b) and that the interaction between Aβ and

the α7 nAChR facilitates the internalization of Aβ in neurons (Nagele et al., 2002).
This reported internalization of Aβ by α7 nAChRs may explain the observation that
Aβ and α7 nAChRs have been found to be colocalized in neurons of AD patients
(Nagele et al., 2002; Wang et al., 2000a,b; Wevers et al., 1999). It has been postu-
lated that the excessive intraneuronal accumulation of Aβ via internalization by the
α7 nAChR leads to neuronal death (Nagele et al., 2002). However, this hypothesis is
not consistent with the observation that α7 nAChRs are not preferentially lost in AD.
3 Diseases Associated with Innate
Differences in the Expression of nAChRs
Although there obviously is individual variability in the expression of brain nAChRs
in the population, altered expression of some nAChRs relative to healthy controls
is associated with several neuropsychiatric disorders. The best-studied example of
low nAChR expression in brain and disease is schizophrenia. A second example
discussed is autism.
3.1 Schizophrenia
Schizophrenia is characterized by multiple symptoms including, but certainly not
limited to, psychosis, apathy, and cognitive impairment (Austin, 2005; Mueser and
McGurk, 2004). Another common feature of schizophrenia is poor sensory inhibi-
tion including the inability to “filter” repetitive stimuli (Baker et al., 1987; Boutros
et al., 1999; Braff et al., 2001; Clementz et al., 1998; Holzman, 2000; Kelley
and Bakan, 1999; Lee and Williams, 2000). The inability to filter repetitive stim-
uli is believed to lead to personality decompensation (Venables, 1964, 1992) and
almost certainly contributes to the cognitive deficits associated with schizophrenia
(Erwin et al., 1998; Simosky et al., 2002). The first evidence that nicotinic recep-
tors may be involved in schizophrenia was the observation that either smoking or
nicotine-normalized deficits in sensory inhibition, as measured by P50 auditory gat-
ing, in schizophrenic patients (Adler et al., 1992). In addition, smoking, nicotine,
or nicotinic agonists more recently have been shown to i mprove cognitive perfor-
mance in schizophrenic patients (Freedman et al., 2008; Harris et al., 2004; Olincy
et al., 2006; Sacco et al., 2005). These apparent “beneficial” effects of nicotinic

agents in schizophrenics may explain the extremely high rate of smoking in this
764 J.A. Stitzel
population. It is estimated that anywhere between 50 and 90% of schizophrenic
patients smoke (Dalack et al., 1998; Hughes et al., 1986; Lohr and Flynn, 1992).
In contrast, smoking rates i n individuals with other mental illnesses are around
25% and the prevalence of smoking in the general population is about 20% (Dalack
et al., 1998; Williams and Ziedonis, 2004). Moreover, schizophrenic patients exhibit
altered smoking behaviors that allow them to extract significantly more nicotine per
cigarette than nonschizophrenic smokers (Tidey et al., 2005).
The first direct evidence that alterations in nicotinic receptor expression might
contribute to schizophrenia was from a study by Freedman and colleagues (1995)
who demonstrated that schizophrenic patients had lower levels of α7nAChRsas
measured by
125
I-αBTX binding and lower levels of α4β2
∗
nAChRs as measured
by [3H] cytisine binding in hippocampus relative to controls. The reduced binding
was the result of both fewer labeled cells and diminished labeling per cell. In addi-
tion to reduced expression in the hippocampus, α7 nAChRs also have been shown
to be decreased in other brain areas of schizophrenic subjects including the reticu-
lar thalamic nucleus (Court et al., 1999) and multiple cortical regions (Guan et al.,
1999; Marutle et al., 1999, 2001). However, the data regarding the expression of
high affinity (predominantly α4β2
∗
nAChRs) is less clear. Results suggest that in
schizophrenic patients, there is a reduction in high-affinity nAChRs in hippocampus
(Breese et al., 2000; Freedman et al., 1995) and no change from controls in thalamus
(Breese et al., 2000;Courtetal.,1999). However, there are conflicting results on the
expression of high-affinity nAChRs in the striatum and cortex of schizophrenic sub-

jects. Some studies indicate that there is an increase in high-affinity receptors in
these brain regions of schizophrenic subjects (Court et al., 2000; Martin-Ruiz et al.,
2003; Marutle et al., 2001) whereas other reports show that high-affinity receptor
binding is lower in these brain regions of schizophrenic patients (Breese et al.,
2000; Durany et al., 2000). Despite the equivocal results for high-affinity receptor
expression in schizophrenia, there is evidence that regulation of this nAChR popula-
tion is abnormal. As mentioned previously, smoking generally leads to a significant
upregulation of α4β2
∗
nAChRs in brain. However, depending upon brain region,
upregulation of high-affinity nAChRs is either absent or substantially reduced in
schizophrenic brain relative to controls (Breese et al., 2000).
Support for a role of both α4β2
∗
and α7 nAChRs in schizophrenia also comes
from pharmacological and animal model data. For example, the α4β2
∗
selective
agonists ABT-418 (Stevens and Wear, 1997) and A-85380 (Wildeboer and Stevens,
2008) and the α7 selective agonist DMXB-A (O’Neill et al., 2003; Simosky et al.,
2001; Stevens et al., 1998) improve innate and drug-induced deficits in auditory
gating in rodents. DMXB-A also has been shown to improve sensory gating and
cognitive function and to reduce negative symptoms in two recent clinical trials
(Freedman et al., 2008; Olincy et al., 2006).
Additional support for nAChRs in schizophrenia largely is based on mouse
genetic models. Mice heterozygous for a null mutation in Chrna7, the gene that
codes for the α7 subunit, exhibit reduced expression of the α7 subunit, poor auditory
gating, and other functional deficits in the hippocampus similar to those observed
in schizophrenic patients (Adams et al., 2008). In addition, a naturally occurring