A Key Regulator of Dendritic Morphology in Supragranular Neocortex Impacts Mismatch Negativity

Abstract

BackgroundCytoskeletal structure and neuronal function are heavily intertwined, and altered pyramidal neuron morphology (e.g., reduced dendritic arbors) has been consistently identified in the neocortex of individuals with psychiatric disorders. A missense mutation in Kalrn (Kalrn-PT) enhances activation of RhoA, a cytoskeletal regulator, and leads to adolescent-onset dendritic regression in supragranular auditory cortex. To investigate the relationship between this spatiotemporally altered cytoskeletal structure and psychiatric-relevant dysfunction, we examine the functional impacts of this genetic mutation, focusing on mismatch negativity - a common biomarker of altered sensory integration that matures across adolescence. MethodsIn Kalrn-PT and littermate wild-type mice, pyramidal dendritic morphology was assessed across primary visual cortex (V1) layers using Golgi staining (n=172 neurons/26 mice). Local field potentials (LFPs) and neuronal spiking were recorded during a visual oddball sequence (n=25 mice). Deviance detection - the rodent neural analogue of mismatch negativity - was analyzed across V1 layers. ResultsKalrn-PT mice exhibit reductions in V1 dendritic length specific to layer 2/3, mirroring observations in post-mortem samples from people with psychiatric disorders. Deviance detection was reduced in LFPs from Kalrn-PT mice and absent in layer 2/3 neurons, despite typical feature selectivity and firing rates. These deficits were accompanied by reduced functional connectivity between visual and frontal areas. ConclusionsThese results highlight alterations in higher-level sensory cortical integration in Kalrn-PT mice and demonstrate that adolescent-onset, disease-relevant structural and functional phenotypes can be linked by a common upstream effector. Further, these alterations appear restricted to supragranular layers, demonstrating an outsized role for Kalrn, particularly longer isoforms, in superficial neocortex.