Histamine H1 Receptor in Basal Forebrain Cholinergic Circuit: A Novel Target for the Negative Symptoms of Schizophrenia?

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 serotoninergic transmission are generally implicated in the pathogenesis of schizophrenia (Fig. 1) [3]. Frustratingly, current typical antipsychotics such as D2-receptor blockers, atypical antipsychotics such as serotonin–dopamine antagonists, 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 integrated [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 withdrawal, and cognitive impairments [6]. Cheng et al. reveal a new mechanism underlying the negative symptoms of schizophrenia, while more questions arise and need to be further investigated.

Fig. 1.

Pathological mechanisms of schizophrenia and further questions 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 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-hydroxytryptamine; 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.

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 consistently 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;Hrh1^fl/fl mice, a conditional 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 sensorimotor gating, anhedonia-like behavior, social withdrawal, and cognitive dysfunction, but showed attenuated hyperlocomotion induced by MK-801. In addition, the typical antipsychotic haloperidol fully reversed the deficit in paired-pulse inhibition but failed to reverse the aberrant social novelty recognition, while the atypical antipsychotics 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 cholinergic 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 imbalance in the PFC. To test this hypothesis, they applied re-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;Hrh1^fl/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 heterogeneous 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 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 schizophrenia. 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 pathogenesis 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;Hrh1^fl/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.