Dopamine plays a central role in SZ pathophysiology (Howes and Kapur, 2009) as shown by rich experimental evidence (Simpson et al., 2010; McCutcheon et al., 2019, 2020; Selten and Ormel, 2023). Current findings underscore dopamine’s central role in CIAS (Slifstein et al., 2015; Simpson and Kellendonk, 2017). The dopamine hypothesis was developed post-hoc to account for the serendipitous discovery of the anti-psychotic effect of some dopaminergic drugs (Carlsson and Lindqvist, 1963; Creese et al., 1996), while genetic support is limited (Edwards et al., 2016). The dopaminergic hypothesis can be summarized as the combination of two main effects: (1) excessive dopamine activity in the mesolimbic pathway (Simpson et al., 2010; Elert, 2014; McCutcheon et al., 2019), specifically in the striatum, disrupts the neurotransmitter balance impairing the functioning of other brain regions involved in cognitive processing; (2) reduced dopamine activity in the mesocortical pathway, connecting the ventral tegmental area (VTA) to the prefrontal cortex (PFC), is linked to both negative symptoms and CIAS (Brisch et al., 2014; Elert, 2014; Slifstein et al., 2015; Simpson and Kellendonk, 2017; Figure 2A). The dual dopamine hypothesis (Elert, 2014; McCutcheon et al., 2020) also opens an issue for the functioning of dopaminergic antipsychotics, whose efficacy is largely linked to their affinity for the D2R distributed both in cortical and subcortical regions (Toda and Abi-Dargham, 2007; Howes et al., 2012; de Bartolomeis et al., 2023). Although the dopamine hypothesis is central to SZ, its dysregulation in the striatum and cerebral cortex is just one aspect of the complex pathophysiology of SZ. The cerebellum, whose dopaminergic system is starting to unveil, is also probably key to CIAS, as explained below.

Another relevant system for SZ is the cholinergic one. Ach plays a vital role in cognitive functions, and pharmacological manipulation targeting the Ach system influences attention, episodic, working, and spatial memories (Newman et al., 2012). Several experimental results converge toward the hypothesis of cholinergic hypofunctioning (Figure 2B) in SZ. Indeed, notable changes in the cholinergic system linked to CIAS, including (1) reduced cholinergic activity, (2) altered receptor functions (especially M1 and M4 mAChRs) (Crook, Tomaskovic-Crook et al., 2000, Carruthers et al., 2015), and (3) disrupted cholinergic-dopaminergic interactions (Foster et al., 2021). Although direct evidence on cerebellar cholinergic alterations in CIAS is scarce, its investigation could open new potential avenues.

Another neurotransmitter implicated in CIAS is serotonin or 5-hydroxytryptamine (5-HT) (Eggers, 2013). Extensive evidence points to serotonergic hypofunctioning, suggesting that targeting the serotonin system might provide a viable treatment for CIAS. Thus, a comprehensive understanding of the mechanisms involved is crucial for designing effective treatments (Figure 2C). The conflicting findings on serotonin alterations, high level (Zhang et al., 2011), low 5-HT2 receptor density, and altered enzyme activity underscore the complexity of its role in CIAS, suggesting potential treatments through serotonin system modulation. However, there are still gaps in understanding broader neural circuits beyond the forebrain and midbrain regions, crucial for addressing cognitive deficits. Thus, considering the serotonergic system in cerebellum (Oostland and van Hooft, 2013) and its influence on other neurotransmitters, consequently, cognitive processes, might further reveal how serotonin dysfunction interacts with CIAS (Section 3.2.3).

The incomplete effectiveness of current antipsychotics suggests that alterations in these systems do not account for most of the negative and cognitive symptoms. Therefore, a glutamatergic model of SZ has been proposed. Elert attributed altered concentrations of dopamine in different brain regions to glutamate dysregulation (Elert, 2014), specifically, glutamate receptors in SZ patients are compromised preventing glutamate from binding to them and dysregulating the function of GABAergic inhibitory interneurons. The lack of inhibition, eventually, causes excessive dopamine in the nucleus accumbens, resulting in positive symptoms of SZ, and reduced dopamine concentration in PFC, leading to negative symptoms (Elert, 2014) (please note that, in Elert’s work, cognitive symptoms are considered together with the negative ones). Extensive evidence, combined with preclinical findings, supports the notion that alterations in the glutamatergic system, including neurotransmitter and transporter high levels in different brain regions (Matute et al., 2005; Merritt et al., 2019, 2021; Adams et al., 2022) and reduced NMDAR function (NMDAR hypofunction) (Gonzalez-Burgos and Lewis, 2012; Moghaddam and Javitt, 2012), play a crucial role in the development of CIAS, thus placing the glutamate system dysfunction at the core of SZ (Swanton, 2020; Figure 2D). Experimental evidence points also to GABAergic system alteration in SZ (Fatemi and Folsom, 2015). Specifically, Glutamic Acid Decarboxylase 67 (GAD67) downregulation (Fatemi et al., 2005; Gonzalez-Burgos and Lewis, 2012; Fujihara, 2023), low GABA level (Nakahara et al., 2022), receptor hypofunction (Marques et al., 2021) and downregulation, and transmission deficits are linked to CIAS (Dienel et al., 2023), emphasizing the potential of targeting the GABAergic system for improving CIAS. For a review of the glutamatergic and GABAergic hypothesis together see Yeganeh-Doost et al. (2011). Given the fundamental role of the glutamatergic and GABAergic systems of cerebellum, these will be considered below for their potential contribution to CIAS (Sections 3.2.4, 3.2.5).

Based on glutamatergic and GABAergic alterations, an altered E/I balance can eventually explain CIAS (Jelen et al., 2019, Liu et al., 2021, Gawande et al., 2023). Restoring the E/I balance and addressing abnormalities in glutamatergic and GABAergic neurotransmission may offer a potential target to improve cognitive function. In particular, the cerebellar E/I balance, potentially involved in various cognitive processes (Sections 1.2, 1.3 in Supplementary material), is a strong candidate to explore CIAS.

Pharmacologically, multiple strategies are exploited to attack the neurotransmitter systems from different sites to ameliorate SZ positive and negative symptoms. The main drugs used are called typical (e.g., haloperidol and chlorpromazine) or atypical (e.g., olanzapine and risperidone), depending on whether they act on the dopaminergic system or also/exclusively on the others. Typical drugs are dopaminergic inhibitors, mostly acting on D2R, ameliorating the positive symptoms but often worsening the negative ones. Given their poor selectivity, these drugs also lead to side effects, including extrapyramidal disturbances, hyperprolactinemia, cognitive decline (Li et al., 2016; Orzelska-Górka et al., 2022), sedation, and cardiovascular issues (Stępnicki et al., 2018). Atypical antipsychotics, instead, address both positive and negative symptoms by affecting various other receptors and have fewer side effects. This is potentially due to their lower D2R affinity or to their preference for mesolimbic over nigrostriatal pathway receptors (Stępnicki et al., 2018; Orzelska-Górka et al., 2022). Consequently, attempts to address cognitive and negative symptoms are growing, rather than exclusively targeting D2R in the dopaminergic system that mainly ameliorates positive symptoms. While atypical drugs might rescue negative symptoms, their primary efficacy remains in targeting positive ones. We argue that recent knowledge on cerebellar physiology will allow for considering new avenues for antipsychotic drug actions and neuromodulation (e.g., transcranial magnetic stimulation, TMS) in CIAS (Section 4.2).

As seen above, dopamine in forebrain circuits is crucial for cognitive functioning and is significantly implicated in SZ pathophysiology (Davis et al., 1991; Kesby et al., 2018) (Section 2.1). A fact that has not been sufficiently recognized before is that dopamine is also present at high concentrations in the cerebellum. In rodents, the deep cerebellar nuclei (DCN) show higher dopamine concentrations than hippocampus and cerebellar cortex, and similar to frontal cortex (Versteeg et al., 1976). Several clinical and preclinical studies showed a crucial involvement of cerebellar dopaminergic mechanisms in CIAS (Demirtas-Tatlidede et al., 2010; Rogers et al., 2013; Parker et al., 2014).

Recently, the cerebellar dopaminergic system has been characterized. Receptor subunits D1R-D5R have been reported in various lobules of the cerebellar cortex, mostly in PCs, where they impact synaptic and cellular plasticity (Cutando et al., 2022). Dopaminergic projections to the cerebellar cortex and nuclei originate mainly from VTA (Ikai et al., 1994) and in part from locus coeruleus (Canton-Josh et al., 2022) that also gives rise to the major dopaminergic midbrain and cerebral pathways (Panagopoulos and Matsokis, 1994). Moreover, PCs produce dopamine (Li et al., 2023). Finally, the cerebellum output through the DCN regulates the VTA (Carta et al., 2019) and the substantia nigra (Washburn et al., 2024). Therefore, the cerebellum has a triple relationship with the dopaminergic system: it produces dopamine, it receives dopaminergic innervation, and it regulates the dopaminergic systems of the brain stem and basal ganglia.

PCs synthesize and release dopamine in an activity-dependent manner modifying local microcircuit functioning (Li et al., 2023). Dopamine binds to D1Rs in Bergman glial cells causing membrane depolarization and activating a Ca²⁺ signaling cascade leading to AMPA receptor GluA1 subunits membrane insertion and glutamate release. This, in turn, enhances interneuron activity reducing PC excitation by parallel fibers and climbing fibers (cfs) and altering the PCs firing frequency and pattern, eventually impacting locomotor and social behavior. These findings indicate that the cerebellar dopaminergic system has a critical pathophysiological role in disorders associated with motor and social dysfunction (Li et al., 2023). Axons coming from the locus coeruleus may regulate cerebellar cortex activity by co-releasing dopamine onto D1R-positive unipolar brush cells. PCs, then directly inhibit the same unipolar brush cells, forming a dopamine-sensitive recurrent circuit (Canton-Josh et al., 2022).

The cerebellum modulates VTA dopamine release via direct projections impacting the expectation/reward mechanism (Carta et al., 2019; Holloway et al., 2019). This pathway extends the role of cerebellum in error detection to the discrepancy between motivation and expectation of reward allowing a cerebellar control on emotional and social behavior (D'Angelo, 2019).

As seen above, hypoactivity in the mesocortical pathway is associated with negative symptoms and CIAS (Toda and Abi-Dargham, 2007; Treadway and Zald, 2011). Interestingly, reduced functionality in cerebellar circuits alters dopaminergic activity in the medial PFC (Rogers et al., 2011), suggesting that a third, cerebellum-related, control system impacts dopaminergic functions in SZ. Indeed, electrical stimulation of the Purkinje layer and DN evokes a long-lasting increase in dopamine release in PFC. Thus, a disconnection between the PCs and neuronal populations of the DN could alter dopaminergic signaling in PFC and impact SZ symptoms (Mittleman et al., 2008) and CIAS. Reduced interaction between the cerebellum and the basal ganglia-dopamine network might be involved in regulating the motivation domain (Yoshida et al., 2022).

Indirect evidence supports this hypothesis. (1) In rat cerebellum, the atypical antipsychotic blonaserin and the anxiolytic buspirone engage extensively in D3R regulation and their action is associated with cognitive impairment (Baba et al., 2015; Di Ciano et al., 2017). (2) A reduced cerebellar expression of SP transcription factors and D2Rs was related to negative symptoms observed in SZ (Pinacho et al., 2013). (3) In genomic DNA isolated from the cerebellum, the atypical antipsychotic agent olanzapine increased methylation of genes related to the dopaminergic system, such as D3R, DOPA decarboxylase, and VMAT2 (SCL18A2/VMAT2) (Melka et al., 2013). (4) Alteration in D2R levels in PCs of male mice during adulthood alters sociability and preference for social novelty without affecting motor functions (Cutando et al., 2022). (5) Aberrant dopamine neurotransmission in SZ influences the cerebellar vermis affecting time processing and directly addressing the cognitive dysmetria hypothesis (Yeganeh-Doost et al., 2011). While more research is warranted, a causal link is beginning to emerge between cerebellar dopamine and CIAS.

Cholinergic signaling in the cerebral cortex and basal forebrain is strongly related to learning and memory (Lecrux et al., 2017) (Section 2.1) but its role in the cerebellum is less explored. Nevertheless, there is growing evidence indicating that cholinergic projections from the brainstem may influence cerebellar function and play a modulatory role in cognitive processing. Cholinergic projections form the third afferent system of the cerebellum, following cfs and mfs (de Lacalle et al., 1993), and seem to play a modulatory role by biasing neuronal excitability and synaptic responses, eventually influencing the cerebellar output and behavioral responses (Zhang et al., 2016).

Nearly half of cholinergic neurons in the brainstem project to cerebellum (Zhao et al., 2023). The vermis also harbors a substantial population of cholinergic neurons, and a dysfunction in this region may potentially contribute to cognitive deficits (Huang et al., 2007), as observed in Parkinson’s disease patients (Maiti et al., 2020). Both nAChRs and mAChRs are expressed in the cerebellum and are activated by Ach released from cholinergic fibers.

In rodents, mAchRs are present in all cerebellar lobules with differential expression across layers. Expression is higher in the PC layer of lobules I-V, Crus I-II, in the GC layer of lobules VI-VII, and in the molecular layer of all other lobules. Cholinergic fibers emerge from the inferior peduncle and spread across the cerebellar cortex as mfs, glomerular rosettes, and thin varicose fibers (Jaarsma et al., 1997). The cerebellum shows choline acetyltransferase (ChAT) (Jaarsma et al., 1997) and acetylcholine esterase (Okkels et al., 2023) activity, and [¹⁸F] FEOBV PET imaging have revealed Ach uptake in the cerebellum in vivo, most markedly in the vermis and flocculonodular lobe (Okkels et al., 2023).

The α7-nACh receptor subunit controls LTD/LTP balance at mf-GrC synapses, which, consequently, facilitates neural adaptation (Prestori et al., 2013). Similarly, applying nicotine during an air-puff stimulation task influences GrCs activity (Xu et al., 2019). Cerebellar nAChRs can also regulate GABA release from interneurons in a subtype-specific manner and affect cognitive functions (Turner et al., 2011).

Alterations of the cerebellar cholinergic system were documented in various mental disorders and associated with cognitive decline. For instance, in a rat model of Japanese encephalitis characterized by marked damage in cognitive functions, transient spatial learning and memory deficits were due to reduced cholinergic activities in various brain regions including the cerebellum (Chauhan et al., 2016). The reduction involved most cholinergic markers, including total muscarinic receptor bindings and M2 receptor, CHRM2 mRNA level, and ChAT expression (Chauhan et al., 2016).

Ach plays a crucial role in the cerebellar interpositus nucleus during execution and coordination of voluntary movements, through activation of muscarinic receptors. Moreover, the cholinergic system is relevant for reward-related behavior (Pickford et al., 2023). Bilateral cerebellar infusion of scopolamine (mAChR antagonist), or Mecamylamine (mAChR antagonist) differentially impaired motor performance (Pickford et al., 2023). Disruption in cholinergic neurotransmission has been associated with executive dysfunction in animals and humans affected by SZ (Section 2.1). While there is currently no direct evidence evaluating the role of cerebellar cholinergic signaling in CIAS, alterations in the cholinergic system might impact CIAS. For instance, individuals with SZ often experience cognitive impairments in working memory, attention, and executive functions, all of which have been associated with cerebellar activity and cerebellar cholinergic signaling. These observations are indirect and further research is required to elucidate the relationship between cerebellar cholinergic dysfunction and CIAS.

Serotonergic signaling regulates mood, cognition, and various physiological processes, and its alteration is implicated in SZ pathophysiology (Section 2.1). Although serotonin is commonly associated with PFC and limbic system, it is also present in the cerebellum (Oostland and van Hooft, 2013), and serotonergic fibers represent one of the primary input pathways. Cerebellar 5-HT modulates glutamatergic and GABAergic synaptic transmission, regulates signal flow in PCs, facilitates firing, and regulates synaptic transmission and long-term synaptic plasticity in DCN neurons (Saitow et al., 2013). In the cerebellar cortex and DCN, different subtypes of serotonergic receptors (5-HT₁B, 5-HT₂B, 5-HT₂A, 5-HT₃, and 5-HT₅A) have been identified (Duxon et al., 1997; Oostland and van Hooft, 2013).

The serotonergic system controls cerebellar development and is implicated in neurodevelopmental diseases (Oostland and van Hooft, 2013). Initially, 5-HT regulates dendritic growth and synaptic plasticity. In the first postnatal week, activation of 5-HT₁R expressed by GrCs and PCs stimulates dendritic growth and synapse formation (Oostland et al., 2014). Then, activation of 5-HT₃ Rs in GrCs limits dendritic growth of PCs by modulating pf-PC plasticity and cf competition for PC dendrites. Finally, activation of 5-HT₂R in GrCs and PCs during late postnatal development and in the mature cerebellum stabilizes synaptic activity (Oostland and van Hooft, 2013; Oostland et al., 2014). The Lugaro cells are also specifically targeted by serotonergic inputs that can increase their firing thereby inhibiting Golgi cells (GoC) (Dieudonné and Dumoulin, 2000).

Under physiologic conditions, cerebellar 5-HT₁ARs decline during the neonatal stage and disappear by early childhood. In contrast, in SZ, cerebellar 5-HT₁ARs persist in adulthood, specifically in the vermis, in relation to abnormal serotonergic innervation (Slater et al., 1998). These results support the notion that SZ has a neurodevelopmental component and that cerebellar 5-HTRs expression goes wrong during ontogenesis. This aspect is intriguing since 5-HT₁AR is strongly associated with disturbed mood and emotion (Popova and Naumenko, 2013). Upregulation of cerebellar 5-HT₁AR in SZ has been confirmed by in vivo PET imaging (Tauscher et al., 2002) while immunolabeling revealed that cerebellar 5-HT₂AR is reduced in SZ subjects (Eastwood et al., 2001).

The reported alterations in 5-HTR expression in the cerebellar cortex and nuclei contribute to the serotonergic hypothesis of SZ, although a direct demonstration is still lacking. Please note that altered cerebellar serotonergic signaling is potentially associated with ASD, where a broad distribution of 5-HT₅A mRNA has been revealed in all cerebellar regions (Marazziti, 2002).

Alterations of the glutamatergic system in SZ (see Section 2.1) have been reported not just in the basal ganglia, temporal lobe, and thalamus (Merritt et al., 2023) but also in the cerebellum. The cerebellum contains the highest concentration of NMDA receptors in the brain along with a rich variety of receptor subtypes and receptor-dependent mechanisms. A recent preclinical study suggested the crucial role of cerebellar glutamatergic neurotransmission during brain development in motor and social behavior (van der Heijden et al., 2023).

Cerebellar NMDARs are crucial for neuronal survival (Contestabile, 2002) and circuit development and functioning (Rabacchi et al., 1992; Bidoret et al., 2009). Repeated ketamine administration causes neurodegeneration in the cerebellum and memory loss in rats (Onaolapo et al., 2019). PCP administration during the neonatal stage impacts development of the olivocerebellar circuit. In the PCP model, the mRNA levels of two GoC selective NMDAR subunits, NR2B and NR2D, decreased (Bullock et al., 2009). In humans, in the first episode of psychosis, individuals displayed elevated levels of glutamate both in the associative striatum and cerebellum (de la Fuente-Sandoval et al., 2013). All NMDAR subunits are expressed in the cerebellum, with significant expression of GluN2C and GluN2D (Thompson et al., 2000), and might be altered in SZ (Schmitt et al., 2010).

Alterations in cerebellar NMDAR expression and activity were implicated in cerebellar circuit dysconnectivity and strongly correlated with CIAS (Yeganeh-Doost et al., 2011). The expression of the NR2C subunit in mature mf-GrC synapses (Mullasseril et al., 2010) is regulated by NRG1 (Ozaki et al., 1997), which is a vulnerability gene for CIAS (Douet et al., 2014). In addition, D-serine deregulation is significantly implicated in CIAS (Ma et al., 2019). D-serine, a co-agonist of NMDAR on the glycine binding site (D'Angelo et al., 1990), is oxidized by D-amino acid oxidase (DAO/DAAO), which can regulate the NMDAR function via D-serine breakdown. DAAOs are expressed mainly in cerebellum with little expression in the frontal cortex (Benzel et al., 2008; Jagannath et al., 2017).

In SZ subjects, a reduced expression of the monomeric form of mGluR5 was specifically revealed in the lateral cerebellum and associated with mood disorders in SZ (Fatemi et al., 2013; Matosin et al., 2014; Fatemi and Folsom, 2015).

Moreover, histological alterations were observed in cerebellar slices in a ketamine-induced SZ model in mice; the changes were seen mostly in neurodegenerating cerebellar areas, particularly in PCs showing apoptosis with pyknotic nuclei, irregular dark cytoplasm, and wide interstitial spaces around the cells. This effect was reversed in groups treated with Carpolobia lutea G. Don extract and clozapine (Omeiza et al., 2023). Notably, the recovery of tissue damage was associated with mitigation of positive, negative, and cognitive symptoms.

GABA is the main inhibitory neurotransmitter in the cerebellum and the entire brain (Section 2.1). In the cerebellum, GABA helps regulate and balance neural activity, contributing to motor control, coordination, and cognitive functions. It was hypothesized that, in the cerebellum, the effectiveness of the GABAergic inhibitory system might be reduced in SZ to counterbalance NMDAR hypofunction (Yeganeh-Doost et al., 2011) contributing to cognitive impairment (Piras et al., 2019). The cellular density of GABAergic Purkinje inhibitory neurons in cerebellum is decreased in psychotic patients (Maloku et al., 2010).

Early findings from clinical and preclinical trials showed alterations in cerebellar GABA signaling in SZ patients. The mRNA and protein levels of GABA synthesizing enzymes GAD67 and reelin, which are expressed in GABAergic interneurons, were downregulated (Guidotti et al., 2000; Fatemi et al., 2005; Bullock et al., 2008). Like other neuromodulators, the alterations were not limited to receptor function and expression but also involved GABA levels. A higher concentration of cerebellar GABA was detected in SZ patients, and this was associated with lower phonemic fluency and a reduced number of switches between subcategories compared to healthy subjects (Piras et al., 2019). GAD56 and the presynaptic GABA transporter GAT-1 were also reduced along with PC density (Bullock et al., 2009; Maloku et al., 2010).

GABA_AR containing α6 subunits (α6GABAARs) are located at cerebellar GoCs-GrCs synapses and extra-synaptic sites, where they regulate the precision of inputs required for cerebellar timing (Mapelli et al., 2014; Mapelli J. et al., 2022). These receptors have an impact on motor activity and are involved in cognitive processing and adequate responses to external stimuli in the cerebellum, eventually implicated in CIAS (Lee et al., 2022). The α6GABAARs were upregulated in post-mortem cerebellar tissues and in a rat model induced by PCP (Bullock et al., 2009).

Dysfunction in cerebellar GABAergic interneurons leads to reduced synchronization across brain regions, affecting cortical information processing (Yeganeh-Doost et al., 2011). The specific impairment of subsets of cerebellar GABA-expressing interneurons in SZ (Piras et al., 2019; Lee et al., 2022) could disrupt the coordination between cerebellum and cortex contributing to neuropsychological deficits (Piras et al., 2019).

The cerebellum forms extensive connections with the forebrain via DCN and thalamus generating cerebello-thalamo-cortical circuits (CTCCs) that are thought to underly cognitive and affective functions (Schmahmann, 2016; Ribeiro and Sherrard, 2023). Functionally, the cerebellar and cerebral systems work in concert to refine the timing of neural operations (Castellazzi et al., 2014, 2018; Palesi et al., 2015, 2017, 2018; Bohne et al., 2019; Fujita et al., 2020; Pisano et al., 2021; Li Y. et al., 2022) (see Supplementary material). Through the thalamus, the cerebellum is implicated in coordinating the coherence of oscillations between cerebral cortical structures (Popa et al., 2014; Gambosi et al., 2023; Heck et al., 2023). The cerebellum, as part of the CTCC, performs an error-detection duty and works as a modulator of cognitive information acquired from the cortex (Bang et al., 2018). SZ was early hypothesized to arise from a disrupted CTCC communication impairing the error detection function of the cerebellum (Andreasen et al., 1998; Andreasen and Pierson, 2008; D'Angelo and Casali, 2012), and a wealth of studies have recently focused on abnormal CTCC connectivity as a core pathology of SZ as well as other psychiatric disorders (Okugawa et al., 2004; Koch et al., 2010; Bang et al., 2018; Hanaie et al., 2018; Wang et al., 2018; Ding et al., 2019; Kim et al., 2021; Park et al., 2021). Lesions of the posterior cerebellum have been related to cognitive dysmetria and CIAS (Yeruva et al., 2021). A seminal work revealed the functional connectivity of DN with whole-brain and its association with cognitive impairments and other psychotic symptoms in patients with drug-naïve and first-episode SZ (Xie et al., 2021). The increased connectivity of DN with the bilateral postcentral gyrus and decreased connectivity of DN with the right inferior temporal gyrus and regional cerebellum (e.g., Vermis IV, V, and Crus I) were correlated with CIAS. The other hub of the CTCC is the thalamus, and altered functional connectivity between cerebellar hemispheres, mediodorsal nucleus, and lateral geniculate nucleus of the thalamus was reported in SZ (Collin et al., 2011; Liu et al., 2011; Chen et al., 2013; Anticevic et al., 2014; Barch, 2014).

Both in first-episode and chronic SZ patients, altered cerebellar functional connectivity in RS fMRI was observed with broad cerebral regions, including association networks, the sensorimotor network, the limbic network, basal ganglia network, and the DMN (Liu et al., 2011; Chen et al., 2017; Guo et al., 2018; Zhuo et al., 2018; Xie et al., 2021; Feng et al., 2022). Critical connector hubs were identified using voxel-based analysis in the cerebellum, midbrain, thalamus, insula, and calcarine sulcus, with connectivity to multiple RS networks affected in SZ (Yamamoto et al., 2022). These findings were supported by cognitive task-dependent fMRI, in which SZ patients showed significantly increased connectivity between the cerebellum and left lateral parietal cortex compared to healthy participants (King et al., 2023). Reduced blood flow in the CTCC during cognitive tasks in SZ was related to deficits in cerebellar inhibition of the DCN (Daskalakis et al., 2005). The strength of functional connectivity between the cerebellum and lateral parietal regions, such as the postcentral gyrus and supramarginal gyrus, was associated with negative symptoms, including socio-cognitive dysfunctions and cognitive decline in SZ (Guo et al., 2018; Brady et al., 2019; Park et al., 2021; Choi et al., 2023).

The cerebellum sends monosynaptic glutamatergic projections to dopaminergic and non-dopaminergic neurons of substantia nigra pars compacta (Washburn et al., 2024). Moreover, the cerebellum and striatum communicate with the thalamus and cortex via monosynaptic and polysynaptic connections, producing cortico-striatal-thalamic-cerebellar (CSTC) loops. Associative CSTC subdivisions showed consistent brain-wide bi-directional changes in SZ, hyperconnectivity with sensory cortices, and hypoconnectivity with association cortex. Such alterations were strongly related to cognitive impairment (Ji et al., 2019). A study of resting-state networks in SZ patients showed increased functional connectivity in the DMN associated with decreased connectivity in the cerebellar network (Rong et al., 2023). Connectivity of the cerebellum with basal ganglia and regions involved in visual, sensorimotor processing and reward was also altered (Yoshida et al., 2022).

The cerebellum is connected to and transmits direct stimulatory signals to the VTA, a brain region responsible for the elaboration of rewarding experiences. Optogenetic activation of the cerebellum-VTA connections led to a sense of reward. In the three-chambers social task, these connections become more active when the animal engages with the social chamber during exploration. These data define a major, previously unappreciated role of the cerebellum in controlling the reward circuitry and social behavior, indicating that the cerebellum may mediate SZ symptoms through abnormal connections with the midbrain dopamine brain regions, such as VTA (Carta et al., 2019). Interestingly, recent RS fMRI imaging findings from first-episode SZ patients showed decreased static and dynamic functional connectivity of VTA and substantia nigra pars-compacta to cerebellar vermis (lobules VII and IX), thalamus, striatum, prefrontal lobe, and cingulate gyrus (Xue et al., 2023).

The cerebellum fetal development endures during childhood and influences the postnatal maturation of multiple cortical regions (Wang et al., 2014). Alterations in this process might, in turn, impact on SZ. Indeed, a combined volume reduction in cerebellum (lobules I–V, VIII) and sensorimotor cortex are associated with increased SZ externalizing symptoms (Miquel et al., 2019). Moreover, reduced grey matter volumes in cerebellum and functionally coupled cortical regions are associated with psychiatric symptoms in mid-childhood (Hughes et al., 2023). Interestingly, altered functional connectivity between cerebellum and medial PFC in SZ patients was linked to high childhood trauma scores (Dauvermann et al., 2021). Moreover, increased connectivity between left lateral parietal cortex and cerebellum was correlated with low-grade systemic inflammation and high plasma IL-6 level, higher childhood neglect, and increased DMN connectivity (King et al., 2023). Therefore, the main genetic and epigenetic factors of SZ may also act on the cerebellum driving a cascade of effects impacting the pathogenesis of the disease.