EARLY Α-SYNUCLEIN PATHOLOGY IN THE LOCUS COERULEUS DISRUPTS NORADRENERGIC CIRCUITS AND HIPPOCAMPAL FUNCTION IN A PRODROMAL PARKINSON’S DISEASE MODEL

Although the clinical hallmark of Parkinson’s disease (PD) is classically defined by motor impairment, non-motor symptoms such as cognitive and mood disturbances are now recognised as a critical early component of the disease. These features may precede motor manifestations by years and are strongly associated with dysfunction of the locus coeruleus (LC), the brain’s main source of noradrenaline (NA). The LC is among the earliest regions to develop Lewy pathology and neurodegeneration, and its impairment disrupts NA modulation of neuronal circuits, including dopaminergic networks. We set up a mouse model based on targeted overexpression of human α-synuclein (aSyn) in the LC by stereotaxic viral vector injection. Our aim was to characterise behavioural, functional, and structural alterations driven by dysregulation of the LC–NA system, both locally and in projection areas such as the hippocampus (HC). Behavioural analyses revealed deficits in spatial learning and aversive memory, consistent with prodromal cognitive and emotional alterations in PD. At a structural level, aSyn mice showed aSyn spreading in LC projection regions, and phosphorylated aSyn accumulation in the LC, as well as disruption of the NA fibre network in the HC and increased GFAP‑immunoreactive area in both LC and HC. In parallel, we evaluated hippocampal long-term potentiation (LTP) as a measure of synaptic plasticity and circuit function potentially affected by noradrenergic dysregulation. Overall, this work supports a key role for early LC dysfunction in non-motor PD alterations and support the noradrenergic circuit as a potential target for early intervention in the disease.