Clinical Neuroscience

Faulty fences: Blood-brain barrier dysfunction in schizophrenia

Current Psychiatry. 2022 October;21(10):28-32 | doi: 10.12788/cp.0278

References

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BBB permeability also results in a certain pattern of leukocyte and cytokine activity. Interleukin-1 (IL-1), IL-6, and tumor necrosis factor–alpha can all cross the BBB during neuroimmune inflammation,¹⁰ but there are abnormal heightened and sustained responses of these molecules in schizophrenia. IL-6 is a proinflammatory cytokine in both acute and chronic inflammation that is expressed by astrocytes, endothelial cells, and microglia.¹⁵ IL-6 and its soluble receptor are both elevated in schizophrenia and are associated with white matter degeneration^16,17 and an increase in vCAM1.¹⁵ This implies that while neuroinflammation in schizophrenia is occurring, additional leukocytes are being recruited and secreting their own cytokines in a chronic destructive positive feedback loop. Meanwhile, atypical IL-10 levels can no longer maintain balanced levels of inflammatory molecules,¹⁶ which leads to reduced control of inflammation.

Genetics and immunohistochemistry suggest that the BBB allows the passage of excess B cells and T cells in schizophrenia. Cytokines from WBCs or the BBB during inflammation recruit these additional infiltrating lymphocytes. In gene-wide association studies, there are several genes in schizophrenia important for B cells and T cells in addition to inflammation that interact in a proinflammatory network.¹⁶ These cells are also diffusely found in the white matter¹⁸ and hippocampal tissue¹⁹ of patients with schizophrenia. Taken together, an increase in adhesion molecules, WBCs, and cytokine crosstalk supports a leaky BBB as an important component of the inflammatory model of schizophrenia.

The role of microglia in BBB dysfunction

The effect of BBB permeability on microglial activation is an important caveat in the current research. Although several reports have linked neuroinflammation to confirmed microglial activation in schizophrenia, there is not enough evidence to claim that the BBB alone is the missing link between these theories. Some research suggests that chronic release of cytokines such as IL-6 from macrophages and T cells could increase migration across the BBB for microglial activation.^16,20 However, positron emission tomography has shown mixed results at best. Translocator protein (TSPO) is expressed by microglia that are actively secreting cytokines.²¹ Researchers tracking TSPO changes in relation to BBB alteration have not seen elevated binding in schizophrenia, change due to stage of disease course, or differentiation from low-grade inflammation.^21-24 Moreover, TSPO may be confounded by antipsychotic use²⁵ and microglial expression did not correlate with any changes in adhesion molecules.¹³ TSPO is not an ideal indicator of microglial activation due to BBB breakdown, but that does not bar the possibility of at least a partial contribution to the development of schizophrenia.

Corsi-Zuelli et al²⁶ created a model that attempts to merge BBB permeability and microglial activation through a different medium—T regulatory cells (TRegs). They write that if TRegs mediate interactions between astrocytes and microglia, their hypofunction would impose a prolonged T cell response. The increased access to a high level of IL-6 and its soluble receptors may keep the TRegs hypofunctional in schizophrenia and promote T cell conversion to inflammatory cell types. Experimentally, TReg induction reversed some psychotic symptoms, and greater TReg expression was associated with fewer negative symptoms.²⁶ In an already insufficient BBB, more access to cytokines and leukocytes would sustain inflammation and microglial secretions.

In addition to the issues described regarding the BBB, the blood-CSF barrier at the choroid plexus may also be insufficient in schizophrenia (Box^27-31).

Box

Choroid plexus permeability in schizophrenia

The choroid plexus’ primary role is to make CSF, but it also secretes cytokines and to some extent serves as a barrier. Unlike the blood-brain barrier (BBB), the blood-CSF barrier is composed of endothelial cells with fenestrations as well as tight junctions, which make the blood-CSF barrier overall more permeable.^27,28 The most unusual finding regarding the choroid plexus in schizophrenia is size. The choroid plexus is physically larger in patients with schizophrenia, and to a lesser extent, in their first-degree relatives.²⁹ A larger choroid plexus is correlated with more severe cognitive symptoms, increased risk for psychosis via biological stress, and significantly higher interleukin-6 (IL-6).^27,29 The increased thickness could be an attempt to compensate for hyperactivity and toxic processes in a permeable environment. More circulating cytokines such as IL-6 and tumor necrosis factor–alpha from microglia can trigger an increase in intercellular adhesion molecule 1, resulting in leukocyte attachment and entry.³⁰ Less claudin-5 at the choroid plexus in schizophrenia implicates similar permissive effects as seen at the BBB.³¹ Although the contribution of blood-CSF barrier dysfunction to schizophrenia requires further study, reduced barrier function outside the BBB is a viable line of inquiry.

Continue to: Caveats about this research