Loss of Clustered Protocadherin Diversity Alters the Spatial Distribution of Cortical Interneurons in Mice

Abstract

Cortical interneurons (cINs) are locally-projecting inhibitory neurons that are distributed throughout the cortex. Due to their relatively limited range of influence, their arrangement in the cortex is critical to their function. cINs achieve this arrangement through a process of tangential and radial migration, and apoptosis during development. In this study, we investigated the role of clustered protocadherins (cPcdhs) in establishing the spatial patterning of cINs through the use of genetic cPcdh knockout mice. cPcdhs are expressed in cINs, and are known to play key functions in cell spacing and cell survival, but their role in cINs is poorly understood. Using spatial statistical analysis, we found that the two main subclasses of cINs, parvalbumin-expressing (PV) and somatostatin-expressing (SST) cINs, are non-randomly spaced within subclass, but randomly with respect to each other. We also found that the relative laminar distribution of each subclass was distinctly altered in whole α- or β-cluster mutants. Examination of perinatal timepoints revealed that the mutant phenotypes emerged relatively late, suggesting that cPcdhs may be acting during cIN morphological elaboration and synaptogenesis. We then analyzed an isoform-specific knockout for pcdh-αc2 and found that it recapitulated the α-cluster knockout, but only in SST cells, suggesting that subtype-specific expression of cPcdh isoforms may help govern subtype-specific spatial distribution.

Reciprocal Connections between Parvalbumin-Expressing Cells and Adjacent Pyramidal Cells Are Regulated by Clustered Protocadherin γ

“…In mice, the 58 cPcdh genes are organized into three gene clusters: cPcdhα , cPcdhβ , and cPcdhγ ( Kohmura et al, 1998 ; Wu and Maniatis, 1999 ). It is now becoming clear that different neuronal cell types express different cPcdh isoforms ( Chen et al, 2017 ; Katori et al, 2017 ; Mountoufaris et al, 2017 ; Gallerani and Au, 2020 ), and in neocortical excitatory neurons, approximately nine cPcdh isoforms are expressed ( Lv et al, 2022 ). It is known that cPcdhs have homophilic binding properties, suggesting their involvement in differentiating between self and other neurons ( Esumi et al, 2005 ; Kaneko et al, 2006 ; Schreiner and Weiner, 2010 ; Hirano et al, 2012 ; Lefebvre et al, 2012 ; Yagi, 2012 , 2013 ; Mountoufaris et al, 2017 ; Rubinstein et al, 2017 ; Brasch et al, 2019 ; Goodman et al, 2022 ).…”