Neurosci. Bull.
cn
https://doi.org/10.1007/s12264-021-00811-8
RESEARCH HIGHLIGHT
Histamine H1 Receptor in Basal Forebrain Cholinergic Circuit:
A Novel Target for the Negative Symptoms of Schizophrenia?
Shuangshuang Wu1 • Chenshu Gao1 • Feng Han2 • Heming Cheng1
Received: 27 September 2021 / Accepted: 7 November 2021
Ó Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences 2021
Schizophrenia is a common and severe mental disorder
with a lifetime prevalence of *1% [1]. Apart from the
typical positive symptoms, such as hallucinations and
delusions, which mainly make patients seek medication,
60%–70% of patients are tortured by negative symptoms
(e.g. apathy and alogia) and cognitive deficits that impose a
long-term burden on patients [2]. Classically, deficits in
mesocortical dopaminergic transmission, prefrontal cortex
(PFC) glutamatergic transmission, and midbrain serotonin-
ergic transmission are generally implicated in the patho-
genesis of schizophrenia (Fig. 1) [3]. Frustratingly, current
typical antipsychotics such as D2-receptor blockers, atyp-
ical antipsychotics such as serotonin–dopamine antago-
nists, and agents targeting multiple receptors have little
effect on the negative symptoms and cognitive deficits,
although they significantly improve the positive symptoms
[4]. The pathological mechanism and potential treatment of
negative symptoms of schizophrenia remain to be inte-
grated [5]. A recent study by Cheng et al. found that a
deficit of the histamine H1 receptor (H1R) in basal
forebrain (BF) cholinergic neurons that project to the
PFC, but not in other regions or other types of neurons,
essentially contributes to behaviors associated with the
negative symptoms of schizophrenia including a deficit in
sensorimotor gating, anhedonia-like behavior, social
& Heming Cheng
chm_1125@126.com
1
Key Laboratory of Neuropharmacology and Translational
Medicine of Zhejiang Province, School of Pharmaceutical
Sciences, Zhejiang Chinese Medical University, Hang-
zhou 310053, China
2 sensorimotor gating, anhedonia-like behavior, social with-
Key Laboratory of Cardiovascular and Cerebrovascular
Medicine, School of Pharmacy, Nanjing Medical University,
Nanjing 211166, China
www.neurosci.
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withdrawal, and cognitive impairments [6]. Cheng et al.
reveal a new mechanism underlying the negative symp-
toms of schizophrenia, while more questions arise and need
to be further investigated.
Numerous studies have shown that the histaminergic
system plays a crucial role in a number of diseases of the
central nervous system including schizophrenia, mainly
through H1Rs [7]. Early studies found that the density of
H1Rs in the frontal cortex is decreased in patients with
chronic schizophrenia [8]. Cheng et al. further reveal that
in schizophrenic patients with both positive and negative
symptoms, Hrh1 mRNA in BF cholinergic neurons but not
in other types of neurons are significantly decreased, and
this is accompanied by decreased expression of choline
acetyltransferase (ChAT), when compared with age-
matched healthy controls and patients with only positive
symptoms [6], suggesting that the H1R level in BF
cholinergic neurons may be correlated with negative
symptoms of schizophrenia. Furthermore, male patients
with both positive and negative symptoms show consis-
tently reduced Hrh1 and ChAT while female patients differ
in having an unchanged level of ChAT. Taking into
consideration the sample size (the numbers of female
patients and patients with only positive symptoms are very
small), more clinical research is needed to confirm the
results of symptom and gender differences.
The authors further studied the function of H1R of
cholinergic neurons in ChAT-Cre;Hrh1fl/fl mice, a condi-
tional knockout (cKO) model. They found that selective
deletion of H1Rs in cholinergic neurons but not in
glutamatergic or dopaminergic neurons in both male and
female mice resulted in several behavioral deficits in
drawal, and cognitive dysfunction, but showed attenuated
hyperlocomotion induced by MK-801. In addition, the
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Fig. 1 Pathological mechanisms of schizophrenia and further ques-
tions yet to be answered. Decreased SN/VTA–PFC dopamine activity
(green), increased SN/VTA–Str dopamine activity (green), decreased
PFC excitatory activity (purple), decreased DR 5-HT activity
(orange), and decreased BF cholinergic activity (red) are considered
to be implicated in the mechanism underlying schizophrenia. Further
questions from the study by Cheng et al. [6] include: (1) What is the
level of H1R in patients with drug-resistant schizophrenia? (2) How
typical antipsychotic haloperidol fully reversed the deficit
in paired-pulse inhibition but failed to reverse the aberrant
social novelty recognition, while the atypical antipsy-
chotics risperidone and clozapine fully reversed both of
them. The distinct effects of these drugs on the negative
symptom-like behavior in schizophrenia may be associated
with the different effects of these drugs on cholinergic
signaling and the diversity of pharmacogenomics. These
results indicate that selective deletion of H1Rs in cholin-
ergic neurons induces behaviors that resemble the negative
symptoms of schizophrenia.
The cholinergic system is closely associated with the
pathogenesis of schizophrenia, and clinical studies have
found that smaller volumes of BF regions containing
cholinergic neurons are linked to the attentional deficits in
schizophrenia [9]. Cheng et al. screened the main regions
of cholinergic neurons and discovered reduced expression
of ChAT as well as a decreased level of acetylcholine
(ACh) in the BF and the PFC but not in the caudate/
putamen (CPu) or the pontomesencephalic (PM) areas in
cKO mice [6]. In addition, putative cholinergic neurons in
the BF showed decreased intrinsic excitability while
putative pyramidal neurons in the PFC showed increased
excitability that were reversed by atypical antipsychotics.
More neuroimaging studies uncovering alterations of
functional connectivity between the BF and PFC in
schizophrenic patients with negative symptoms deserve
further investigation. Here, the authors hypothesized that
deletion of H1R results in hypofunction of BF cholinergic
neurons with subsequent decreased release of ACh in the
PFC, and finally contributes to excitation/inhibition imbal-
ance in the PFC. To test this hypothesis, they applied re-
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Neurosci. Bull.
does deletion of H1R only contribute a decrease of ChAT in the BF
but not in the CPu or PM? (3) Which receptor do BF cholinergic
neurons target in the PFC? Abbreviations: 5-HT, 5-hydrox-
ytryptamine; ACh, acetylcholine; BF, basal forebrain; DA, dopamine;
DR, dorsal raphe; E/I, excitatory/inhibitory; H1R, histamine H1
receptor; PFC, prefrontal cortex; SN, substantia nigra; Str, stratum;
VTA, ventral tegmental area.
expression of H1R in BF cholinergic neurons or direct
activation of the BF–PFC cholinergic circuit in cKO mice,
and found that the behavioral deficits together with
alterations in the excitability of BF cholinergic neurons
and PFC pyramidal neurons were fully rescued. This
indicates that the BF–PFC cholinergic circuit may be
required for negative symptom-like behavior in ChAT-
Cre;Hrh1fl/fl mice. Interestingly, chemogenetic inhibition
of BF cholinergic neurons not only induced negative
symptoms-like behavior, but also aggravated positive
symptom-like behaviors induced by MK-801, totally
contrary to the cKO mice. The authors did not provide
more evidence to explain the paradoxical results, for
example what effect direct modulation of the BF–PFC
cholinergic circuit with optogenetics would have on the
schizophrenia-like behaviors. Considering the heteroge-
neous roles of BF cholinergic neurons, the potential
existence of other cholinergic circuits could be taken into
an account. Above all, Cheng et al. found a novel H1R-
mediated BF–PFC cholinergic circuit which is a substrate
for the negative symptoms of schizophrenia [6].
Current antipsychotics have limited effect on the
negative symptoms of schizophrenia, even though in some
periods, patients with schizophrenia prominently show
negative symptoms [1]. To investigate further therapeutic
potential, Cheng et al. over-expressed H1Rs in BF
cholinergic neurons in the MK-801-induced schizophrenia
model and found that this over-expression selectively
rescues negative symptom-like behavior but not the
hyperlocomotion [6]. It is a pity that the authors did not
study the effect of an H1R agonist directly applied to the
BF in this model and challenges are focused on how to
S. Wu et al.: Histamine H1 Receptor in Basal Forebrain Cholinergic Circuit
develop a drug-delivery system to precisely modulate the
H1R expression in the BF.
In conclusion, Cheng et al. reveal for the first time the
relationship between H1R expression in BF cholinergic
neurons and behavioral deficits associated with schizophre-
nia. It is compelling that the expression of H1R on BF
cholinergic neurons is potentially associated with the
pathogenesis of the negative symptoms, and this further
supplements the theoretical framework for the pathogen-
esis of schizophrenia and provides a reference animal
model of the negative symptoms (Fig. 1). But several
questions remain to be answered. First, does the ChAT-
Cre;Hrh1fl/fl mouse model truly serve as a new model of
negative symptoms of schizophrenia? In this cKO mouse
model, risperidone and clozapine fully reversed the
impairment of social novelty recognition, which is not
consistent with the weak clinical therapeutic effect of
atypical antipsychotics on the negative symptoms of
schizophrenia [10], while other behavioral deficits were
not tested. Besides, the effect of antipsychotics on the BF–
PFC circuit should be considered carefully since they
might have an indirect effect rather than a direct effect,
since the mechanisms are complex and the targets of drugs
are diverse. In parallel, H1R expression in clinical samples
can be further analyzed through being grouped as drug-
effective or drug-resistant. Second, how does deletion of
H1R only give rise to a decrease of ChAT in the BF but not
in the CPu or PM? Considering the vital roles of BF
cholinergic neurons in learning and memory, the H1R is a
promising target to selective modulate BF cholinergic
systems. Third, which receptor do BF cholinergic neurons
target on PFC pyramidal neurons? The cholinergic system
and receptors are novel and potential mechanisms and
therapeutic targets for schizophrenia [9]. Defining the
precise molecular mechanism of the BF–PFC cholinergic
circuit responsible for anti-schizophrenia like behavior will
benefit the development of new antipsychotic drugs.
Conflict of interest The authors declare no conflict of interests.
References
1. McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia-an
overview. JAMA Psychiatry 2020, 77: 201–210.
2. Charlson FJ, Ferrari AJ, Santomauro DF, Diminic S, Stockings E,
Scott JG. Global Epidemiology and burden of schizophrenia:
Findings from the global burden of disease study 2016. Schizophr
Bull 2018, 44: 1195–1203.
3. Cannon TD. How schizophrenia develops: Cognitive and brain
mechanisms underlying onset of psychosis. Trends Cogn Sci
2015, 19: 744–756.
4. Goff DC. The pharmacologic treatment of schizophrenia—2021.
JAMA 2021, 325: 175–176.
5. Bègue I, Kaiser S, Kirschner M. Pathophysiology of negative
symptom dimensions of schizophrenia—Current developments
and implications for treatment. Neurosci Biobehav Rev 2020,
116: 74–88.
6. Cheng L, Xu CL, Wang L, An DD, Jiang L, Zheng YR, et al.
Histamine H1 receptor deletion in cholinergic neurons induces
sensorimotor gating ability deficit and social impairments in
mice. Nat Commun 2021, 12: 1142.
7. Hu WW, Chen Z. The roles of histamine and its receptor ligands
in central nervous system disorders: An update. Pharmacol Ther
2017, 175: 116–132.
8. Nakai T, Kitamura N, Hashimoto T, Kajimoto Y, Nishino N,
Mita T, et al. Decreased histamine H1 receptors in the frontal
cortex of brains from patients with chronic schizophrenia. Biol
Psychiatry 1991, 30: 349–356.
9. Avram M, Grothe MJ, Meinhold L, Leucht C, Leucht S,
Borgwardt S, et al. Lower cholinergic basal forebrain volumes
link with cognitive difficulties in schizophrenia. Neuropsy-
chopharmacology 2021, 46: 2320–2329.
10. Geddes J, Freemantle N, Harrison P, Bebbington P. Atypical
antipsychotics in the treatment of schizophrenia: Systematic
overview and meta-regression analysis. BMJ 2000, 321:
1371–1376.
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