Table 1 Summary of studies included in the systematic review on the cholinergic system in schizophrenia.

Raedler et al., 2003 [4]^a

[¹²³I]IQNB SPECT

Muscarinic Receptors

↓ in cortex, striatum, and thalamus;

~ in the pons.

Lower levels in frontal cortex and striatum associated with ↑ positive (but not negative) symptoms.

12

92%^b

67%

10

17%

Wong et al., 2018 [44]^a

[¹⁸F]-ASEM PET

α7 Nicotinic Receptors

↓ in cingulate cortex and hippocampus;

~ in frontal cortex.

Preliminary association between higher levels and ↑ clinical symptom severity.

6

100%

17%

15

0%

Coughlin et al., 2019 [35]^a

[¹⁸F]-ASEM PET

α7 Nicotinic Receptors

↓ in hippocampus.

Lower levels in hippocampus associated with ↑ cognitive deficits.

5

40%

0%

15

0%

Wong et al., 2024 [43]^a

[¹⁸F]-ASEM PET

α7 Nicotinic Receptors

↓ in hippocampus, striatum, thalamus, and major cortical regions.

Lower levels in hippocampus associated with ↑ positive (but not negative) symptoms and ↑ cognitive deficits.

17

71%

6%

24

0%

Esterlis et al., 2014 [7]^a

[¹²³I]5-IA-85380 SPECT

β2 Nicotinic Subunits

↓ in frontal and parietal cortices;

~ in hippocampus, striatum, thalamus.

Lower levels in striatum, frontal and parietal cortices associated with ↑ negative (but not positive) symptoms.

Lower levels in frontal and parietal cortices associated with ↑ cognitive impairments (smokers).

31

81%

71%^c

31

81%^c

D’Souza et al., 2012 [45]^a

[¹²³I]5-IA-85380 SPECT

β2 Nicotinic Subunits

↓ in frontal and parietal cortices, and thalamus^d;

~ in hippocampus and striatum.

Lower levels in striatum, thalamus, frontal and parietal cortices associated with ↑ negative (but not positive) symptoms.

11

100%

100%^c

11

100%^c

Brasic et al., 2012 [42]

2-[¹⁸F]FA PET

α4β2 Nicotinic Receptors

Inconclusive ↓ in thalamus.^e

5

N.R.

100%

5

20%

Weinstein et al., 2024 [41]^a

[¹⁸F]-VAT PET

Vesicular Transporters

~ brain-wide.

Higher levels in many cortical and subcortical regions associated with ↑ positive symptoms and ↓ cognitive performance.

18

39%

22%

14

7%

Alnafisah et al., 2022 [117]

LCMS-based proteomics

G-protein coupled ACh receptor signaling pathway proteome

↑ in BA9.

23

43%

4%

22

18%

Crook et al., 1999 [118]

[³H]AF-DX 384

M2/M4 Receptors

↓ in caudate/putamen.

19

100%

N.R.

20

N.R.

Crook et al., 2000 [61]

[³H]Pirenzepine

M1/M4 Receptors

↓ in hippocampus.

15

100%

N.R.

18

N.R.

Crook et al., 2001 [108]

[³H]Pirenzepine

M1/M4 Receptors

↓ in BA9, 46, 8^f, and 10^f.

17

100%

N.R.

20

N.R.

Dean et al., 1996 [119]

[³H]Pirenzepine

M1/M4 receptors

↓ in caudate/putamen.

19

100%

N.R.

19

N.R.

Dean et al., 2000 [63]

[³⁵S]oligonucleotide probe

M1 mRNA

~ in caudate/putamen.

14

100%

N.R.

16

N.R.

Dean et al., 2002 [5]

Western Blots

[³H]Pirenzepine

[³⁵S]oligonucleotide probe

M1 Receptors

M4 Receptors

M1/M4 Receptors

M1 mRNA

↓ in BA9; ~ in BA40.

~ in BA9; ~ in BA40.

↓ in BA9; ~ in BA40.

↓ in BA9; ↓ in BA40.

20

85%

N.R.

20

N.R.

Dean et al., 2004 [120]

Western Blots

M1 Receptors

M4 Receptors

~ in mediodorsal nucleus of thalamus.

20

85%

N.R.

20

N.R.

[³H]Pirenzepine

M1/M4 Receptors

~ in thalamus.

In situ hybridization

M1 mRNA

M4 mRNA

Dean et al., 2008 [121]

[³H]4-DAMP

M3 Receptors

~ in BA6.

19

89%

N.R.

19

N.R.

[³H]Pirenzepine

M1/M4 Receptors

↓ in BA6.

Dean et al., 2015 [122]

[³H]Pirenzepine

M1/M4 Receptors

↓ in striatum.

40

90%

N.R.

20

N.R.

[³H]AF-DX 384

M2/M4 Receptors

↓ in striatum.

[³H]4-DAMP

M3 Receptors

~ in striatum.

Dean et al., 2016 [123]

[³H]NMS

Muscarinic Receptors

~ in BA6.

40

95%

N.R.

20

N.R.

Muscarinic Receptor Affinity

↓ in BA6.

BQCA-mediated shift in acetylcholine displacement of [³H]NMS

M1 Positive allosteric modulation

↓ in BA6.^g

Dean et al., 2023 [17]

[³H]Pirenzepine

M1/M4 Receptors

↓ in BA9.

56

≥80%

36%

43

12%

Dean et al., 2024 [124]

[³H]Pirenzepine

M1/M4 Receptors

↓ in BA6.

28

68–75%

36–63%

14

12–42%

Deng and Huang, 2005 [92]

[³H]AF-DX 384

M2/M4 Receptors

↓ in superior temporal gyrus.

8

75%

N.R.

8

N.R.

[³H]Pirenzepine

M1/M4 Receptors

~ (trending ↓) in superior temporal gyrus.

Gibbons et al., 2013 [51]

[³H]Pirenzepine

M1/M4 receptors

↓ in BA10^g, 26^g, 44, 46^g.

38

93%

N.R.

20

N.R.

[³H]AF-DX 384

M2/M4 Receptors

↓ in BA9^g, 10^g, 44^g, 46^g.

[³H]4-DAMP

M3 receptors

↓ in BA9^g, 46^g, 44^g; ~ in BA10.

Hopper et al., 2019 [125]

[³H]NMS

Muscarinic Receptors

↓ in BA6, hippocampus, and striatum.

40

100%^h

N.R.

20

N.R.

BQCA-mediated shift in acetylcholine displacement of [³H]NMS

M1 Positive allosteric modulation

Mancama et al., 2003 [91]

PCR

M1 mRNA

↓ in BA6.

20

N.R.

N.R.

20

N.R.

Matsumoto et al., 2005 [126]

[³H]Pirenzepine

M1/M4 Receptors

~ in BA9, caudate/putamen, and hippocampus.

6

83%

N.R.

6

N.R.

McLeod et al., 2010 [127]

[³H]Pirenzepine

M1/M4 Receptors

↓ in BA9 and B40ⁱ.

20

95%

N.R.

15

N.R.

Newell et al., 2007 [128]

[³H]AF-DX 384

M2/M4 Receptors

↑ in posterior cingulate cortex.

10

100%

N.R.

10

N.R.

[³H]Pirenzepine

M1/M4 Receptors

↓ in posterior cingulate cortex.

Salah-Uddin et al., 2009 [129]

M1 PAM- and muscarinic agonist-stimulated Gα_q/11 to [³⁵S]-GTPγS binding

Efficacy of Receptor-Gα_q/11 coupling

↑ in BA9.^g

20

85%

N.R.

10

N.R.

M1 PAM and Muscarinic Agonist Potency

↓ in BA9.^g

Scarr et al., 2006 [49]

Western blots

M2 and M3 Receptors

~ in BA6 and 40.

18

89%

N.R.

18

N.R.

PCR

M3 mRNA

Scarr et al., 2007 [64]

[³⁵S]oligonucleotide In Situ Hybridization

M1 mRNA

~ in hippocampus.

15

100%

N.R.

15

N.R.

M4 mRNA

↓ in hippocampus.

14

15

[³H]Pirenzepine

M1/M4 Receptors

↓ in hippocampus (except subbiculum).

38

20

Scarr et al., 2009 [116]

[³H]Pirenzepine

M1/M4 receptors

↓ in BA9.

A marked ↓ in BA9 may define a biotype/subgroup.^g

80

33%

N.R.

74

N.R.

Scarr et al., 2013 [90]

PCR

M1 mRNA

↓ in BA9.

69

100%

N.R.

63

N.R.

Seo et al., 2014 [89]

[³H]Pirenzepine

M1/M4 receptors

↓ in BA6.^g

18

100%

N.R.

20

N.R.

[³H]4-DAMP

M3 receptors

~ in BA6.

PCR

M1 mRNA

M3 mRNA

M4 mRNA

~ in BA6.

Toru et al., 1988 [57]^k

[³H]Quinuclidinyl Benzilate

Muscarinic Receptors

↑ in orbitofrontal cortex;

↑ in medial frontal cortex^j;

12^l

50%

N.R.

10^l

N.R.

Watanabe et al., 1983 [130]

[³H]Quinuclidinyl Benzilate

Muscarinic Receptors

↑ in frontal cortex and caudate.^j

12

50%

N.R.

10

N.R.

Muscarinic Receptor Affinity

↓ in frontal cortex and caudate.^j

Zavitsanou et al., 2004 [6]

[³H]Pirenzepine

M1/M4 Receptors

↓ in anterior cingulate cortex.

15

100%

N.R.

15

N.R.

Zavitsanou et al., 2005 [131]

[³H]AF-DX 384

M2/M4 receptors

~ in anterior cingulate cortex.

15

100%

N.R.

15

N.R.

Court et al., 1999 [132]

[¹²⁵I]α-Bungarotoxin

α7 Receptors

↓ in thalamic reticular nucleus;

~ in others.

12

N.R.

N.R.

12

N.R.

Court et al., 2000 [80]

[³H]Cytisine

Nicotinic Receptors

↑ in the striatum.

6

100%

N.R.

42

19%

Dean et al., 2020 [59]^k

[¹²⁵I]α-Bungarotoxin

α7 Receptors

↑ in BA9^g;

~ in BA6 and 44.

27

78%

89%

12

92%

Durany et al., 2000 [79]

[³H]Cytisine

α4β2 Receptors

↓ in striatum.

12

≥58%

N.R.

12

N.R.

Freedman et al., 1995 [54]

[¹²⁵I]α-Bungarotoxin

α7 Receptors

↓ in dentate gyrus and CA3;

~ in CA1.

8

63%

88%

8

38%

[³H]Cytisine

α4β2 Receptors

↓ in the hippocampus.

8

Guan et al., 1999 [133]

[¹²⁵I]α-Bungarotoxin

α7 Receptors

↓ in frontal cortex;

~ in parietal cortex.

8

N.R.

N.R.

8

N.R.

Guillozet-Bongaarts et al., 2014 [134]^k

In situ hybridization & High-throughput analysis

α7 mRNA

↓ in BA9 (layer V);

~ in BA46.

19

N.R.

84%

33

27%

Hemby et al., 2002 [135]

PCR

α7 mRNA

↑ in entorhinal cortex layer II neurons

8

38%

N.R.

9

N.R.

Martin-Ruiz et al., 2003 [62]

[³H]Epibatidine

α2/3/4, β2/4 Subunits

↑ in BA46.

28^l

≥43%

≥54%

14^l

≥21%

PCR

α7 mRNA

~ in BA46.

Western Blots, Immunoreactivity

α7 Receptors

↓ in BA46.

α3, α4, β2 Subunits

~ in BA46.

Marutle et al., 2001 [53]

[¹²⁵I]α-Bungarotoxin

α7 Receptors

↓ in cingulate cortex^m;

~ in orbitofrontal & temporal cortices.

12

58%

25–100%

14^l

64%^l

[³H]Cytisine

α4β2 Receptors

↑ in cingulate & orbitofrontal cortices;

~ in temporal cortex.

[³H]Epibatidine

α2/3/4, β2/4 Subunits

↑ in temporal cortex;

~ in cingulate & orbitofrontal cortices.

Mathew et al., 2007 [136]

[¹²⁵I]α-Bungarotoxin

α7 Receptors

~ in BA46.

27

N.R.

67%

49

71%

PCR

α7 mRNA

~ in BA46.

~ in hippocampus.

30

80%

77%

61

64

74%

31%

Thomsen et al., 2011 [104]

[¹²⁵I]α-Bungarotoxin

α7 Receptors

~ in dentate gyrus, CA3, and CA1 and perirhinal cortex.

13

85%

46–54%

15

20–73%

De Luca et al., 2006 [137]

PCR

α7 mRNA

~ in BA46.

35

100%

N.R.

35

N.R.

Severance and Yolken, 2008 [138]

PCR

α7 mRNA

↓ in corpus callosum;

~ in prefrontal cortex.

35^l

N.R.

74–89%^l

34^l

24–74%

Mexal et al., 2010 [103]

Western Blots

α7 Receptors

~ in hippocampus, but ↑ in patient smokers.

17

88%

59%

18

50%

PCR

α7 mRNA

↓ in hippocampus, but ~ in patient smokers.

18

83%

61%

17

47%

Impagnatiello et al., 1998 [139]

PCR

α7 mRNA

~ in BA46.

8

100%

N.R.

7

N.R.

Kunii et al., 2015 [140]

PCR

α7 mRNA

↓ in dorsolateral prefrontal cortex.

176^l

~63%

N.R.

240^l

N.R.

Dean et al., 2020 [59]^k

Western Blots

ChAT 68/82

~ in BA9.

27

78%

89%

12

92%

Powchik et al., 1998 [48]^a

[³H]/[¹⁴C]acetyl-CoA

ChAT

~ in inferior parietal cortex.

Lower ChAT activity associated with ↑ cognitive impairments.

95

N.R.^h

N.R.

20

N.R.

Haroutunian et al., 1994 [58]

[³H]/[¹⁴C]acetyl-CoA,

[³H]acetylcholine

ChAT, AChE

~ in cortex.

19

N.R.^h

N.R.

9

N.R.

Toru et al., 1988 [57]^k

[¹⁴C]-acetyl-CoA

ChAT

↑ in occipital cortex;

~ in hippocampus and parietal cortex (except ↑ in angular gyrus^j).

11

~41%^l

N.R.

10^l

N.R.

Scarr et al., 2018 [88]

M1 antibodies

M1+ Neurons

↓ in BA9 and 17 (layers III and V);

~ in thalamus and hippocampus.

24

100%

N.R.

12

N.R.

Guillozet-Bongaarts et al., 2014 [134]^k

In situ hybridization & High-throughput analysis

α7+ Cells

↓ in BA9 (layers III–VI);

~ in BA46.

19

N.R.

84%

33

27%

German et al., 1999 [141]

ChAT antibodies

ChAT+ Neurons

~ in mesopontine cholinergic nuclei.

3

N.R.^h

N.R.

6

N.R.

Holt et al., 1999 [47]

ChAT antibodies

ChAT+ Interneurons

↓ in striatum.

11

91%ⁿ

N.R.

9

N.R.

Holt et al., 2005 [46]

[³⁵S]oligonucleotide probe

ChAT mRNA+ Interneurons

↓ in nucleus accumbens; ~ in caudate and putamen.

9

100%

N.R.

11

N.R.