Abstract
While physiological levels of histamine in the developing brain are tightly controlled, genetic mutations or inflammation can result in pathological dysregulation of histaminergic transmission. Dysregulation of histamine is associated with neurodevelopmental disorders such as Tourette's syndrome (TS) and obsessive-compulsive disorder (OCD). Alongside a high heritability, environmental risk factors for Tourette's syndrome are predominantly pre- and perinatal, highlighting early neurodevelopment as crucial in its pathophysiology. Current management is based around using atypical antipsychotics. These are often poorly tolerated with a high burden of metabolic side effects. Therefore, an urgent need to identify new targets for treatment is needed. The mechanisms by which histamine levels control brain development are only just beginning to be understood. Although classically thought of as developmental disorders of the motor circuits of the brain (e.g. the basal ganglia), both disorders show a strong social component where both stress and anxiety can initiate as well as exacerbate symptoms, with an underlying reason remaining largely unknown. In this project, we aim to employ a mouse model of TS/OCD through pharmacological modulation of histamine levels at both pre- and postnatal periods and assess the impact of histamine on the development of a key circuit in the regulation of stress and anxiety responses – the bed nucleus of stria terminal or BNST. Although the focus will be on understanding the impact on developing neurons and neural circuits, we will include assessments of the inflammatory state of the brain and establish whether histamine deficiency leaves the developing brain more vulnerable to proinflammatory insults by altering microglial activation. This will form the basis of further research on whether early intervention using histaminergic drugs or immunomodulatory therapies such as small molecule inhibitors or monoclonal antibodies could have therapeutic benefits on TS.
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