Early synaptic changes and reduced brain connectivity in PD-like mice with depressive phenotype.

Area of Science:

• Neuroscience
• Neurology
• Molecular Biology

Background:

• Anxiety and depression significantly impact Parkinson's disease (PD) patients' quality of life.
• Alpha-synuclein (α-Syn) aggregates in serotonergic (5-HT) raphe nuclei are early PD hallmarks, but their link to brain alterations remains unclear.

Purpose of the Study:

• To investigate synaptic plasticity, neuronal activity, and functional magnetic resonance imaging (fMRI)-based brain connectivity in a PD mouse model exhibiting depressive symptoms.
• To explore the relationship between α-Syn accumulation and early brain changes in emotional circuits.

Main Methods:

• Adeno-associated virus (AAV)-mediated human α-Syn expression in raphe 5-HT neurons of a PD-like mouse model.
• Assessment of synaptic markers (MAP-2, PSD95, SV2A, VAMP2) and neuronal activity (Egr-1).
• Resting-state fMRI to evaluate functional brain connectivity before overt neurodegeneration.

Main Results:

• α-Syn accumulation led to progressive synaptic pathology in interconnected brain regions, evidenced by altered levels of key synaptic proteins.
• Abnormalities in Egr-1-dependent neuronal activity and region-specific resting-state fMRI connectivity were observed eight weeks post-infusion.
• Synaptic and fMRI changes were confirmed in human brain tissue samples, correlating with α-Syn pathology.

Conclusions:

• Early α-Syn pathology in serotonergic neurons induces synaptic dysfunction and altered brain activity in emotional circuits.
• Synaptic and fMRI markers associated with α-Syn pathology can be identified before neurodegeneration.
• These findings have translational implications for identifying Parkinson's disease patients at risk of depression.