CADHERIN 13 REGULATES THE SYNAPTIC MATURATION OF SPECIFIC GABAERGIC INTERNEURONS IN MOUSE VISUAL CORTEX

Cadherin-13 (Cdh13) is a glycosylphosphatidylinositol-anchored cell adhesion molecule and a genetic risk factor for multiple psychiatric disorders. In the forebrain, Cdh13 is localised at GABAergic synapses, but whether Cdh13 plays cell-type specific roles within different cortical GABAergic subtypes is poorly understood.
Here, we investigated the function of Cdh13 in defined populations of GABAergic interneurons and its impact on cortical circuit function and cognition. Single-cell transcriptomic and RNAscope analyses revealed that Cdh13 mRNA is highly enriched in somatostatin-expressing interneurons (SST-INs) in the juvenile and adult mouse cortex. To determine the functional significance of this enrichment, we generated conditional knockout mice in which Cdh13 was selectively deleted either from SST-INs (conditional KO, cKO mice). We observed significant impairments in spatial learning and memory in cKO mice. At the circuit level, cKO mice showed a selective reduction in vesicular GABA transporter (VGAT) intensity within SST-IN axonal boutons in cortical layer 1, without affecting deeper cortical layers, suggesting weakened inhibitory synaptic output of Martinotti cells. Consistent with these structural alterations, whole-cell recordings of connected neurons indicated that Martinotti cell-mediated inhibition was impaired within visual cortical microcircuits in mutant mice. Finally, by using multi-site local field recording, we observed altered visual evoked responses and reduced functional communication between visual and prefrontal cortex during visual stimulation in cKO mice.
Together, these findings suggest that Cdh13 regulates the synaptic maturation of distinct cortical SST GABAergic interneuron subtypes and that Cdh13 expression in SST-IN is necessary for the proper maturation of visual cortical function.