Disrupted ErbB4 splicing with region-specific severity across the cortical visuospatial working memory network in schizophrenia

Abstract

Visuospatial working memory (vsWM) depends on 𝛾-oscillations generated across a cortical network, including dorsolateral prefrontal (DLPFC), posterior parietal (PPC), visual association (V2), and primary visual (V1) cortices. These oscillations require parvalbumin-expressing interneurons (PVIs), and deficient 𝛾-power in schizophrenia (SZ) is thought to reflect reduced PVI activity. Reduction in PVI activity, and activity-dependent PV levels, may result from splicing shift of erb-b2 receptor tyrosine kinase 4 (ErbB4), from major to minor variants that exhibit reduced kinase activity. To investigate whether this relationship is region-specific in the vsWM network of SZ, we performed quantitative PCR and measured ErbB4 splice variants and PV mRNA levels in DLPFC, PPC, V2, and V1 from 16 matched SZ and unaffected comparison (UC) subjects. In UC, major variants were increasingly enriched from rostral to caudal regions. In SZ, this gradient was disrupted by abnormal shifts toward minor variants, with greater shifts in more caudal regions. Moreover, positive association between ErbB4 splicing shift and PV levels was observed only in V1 in UC, but emerged more rostrally and strengthened along the rostral-to-caudal axis in SZ. Thus, disruption of a normally localized mechanism regulating PVI activity may abnormally expand along the rostral-to-caudal axis, contributing to network-wide dysfunction in SZ.

Keywords: NRG1-ERBB4 signaling; alternative splicing; parvalbumin interneuron; schizophrenia; working memory network.