PhD Seminar – Joechen Roeper

Schizophrenia (SCZ) is associated with presynaptic dopaminergic (DA) hyperactivity, particularly in the associative striatum. However, direct mechanistic insights from preclinical models have remain limited. Here, we present the first direct evidence of elevated baseline nigrostriatal dopaminergic activity in a mouse model of the highest known genetic risk factor for SCZ, the 22q11.2 microdeletion. The Df(16)A+/- mouse model, which harbors a hemizygous chromosomal deletion on chromosome 16 syntenic to the human 22q11.2 locus, showed selective hyperactivity in the medial substantia nigra (mSN) DA neurons of both sexes during chronic in vivo single-unit recordings in freely moving animals, in the absence of pharmacological manipulations. Chemogenetic tagging refined the specific hyperactive DA subpopulation within the mSN revealing that this hyperactivity was confined to DA neurons projecting to the dorsomedial striatum (DMS). DA release dynamics with dLight fiber photometry confirmed elevated DA release specifically in the DMS. Projection-resolved single-nucleus RNA sequencing uncovered the upregulation of the NMDA subunit Grin2c and downregulation of the voltage-gated sodium channel modulator Fgf12 in DMS-projecting DA neurons in Df(16)A+/- mice. In vitro patch-clamp recordings further confirmed functional impact on excitability. Our findings reveal the specific locus of a baseline hyperdopaminergic state within DMS-projecting mSN neurons of Df(16)A+/- mice and provide molecular mechanistic insights linking SCZ genetic risk to dopaminergic dysfunction in defined nigrostriatal subcircuits.