Muskelin regulates actin-dependent synaptic changes and intrinsic brain activity relevant to behavioral and cognitive processes

Abstract

Muskelin (Mkln1) is implicated in neuronal function, regulating plasma membrane receptor trafficking. However, its influence on intrinsic brain activity and corresponding behavioral processes remains unclear. Here we show that murine Mkln1 knockout causes non-habituating locomotor activity, increased exploratory drive, and decreased locomotor response to amphetamine. Muskelin deficiency impairs social novelty detection while promoting the retention of spatial reference memory and fear extinction recall. This is strongly mirrored in either weaker or stronger resting-state functional connectivity between critical circuits mediating locomotor exploration and cognition. We show that Mkln1 deletion alters dendrite branching and spine structure, coinciding with enhanced AMPAR-mediated synaptic transmission but selective impairment in synaptic potentiation maintenance. We identify muskelin at excitatory synapses and highlight its role in regulating dendritic spine actin stability. Our findings point to aberrant spine actin modulation and changes in glutamatergic synaptic function as critical mechanisms that contribute to the neurobehavioral phenotype arising from Mkln1 ablation.

Gene expression in the primate orbitofrontal cortex related to anxious temperament

“…Muskelin 1 ( MKLN1 ) was inversely associated with individual differences in AT. Deletion of this gene in rodents has been shown to decrease dendritic spine stability and branching ( 45 ) and was also linked to early-onset bipolar disorder in a recent GWAS ( 46 ). Neural cell adhesion molecule 1 (NCAM1) was positively associated with individual differences in AT.…”

Tspan15 depletion in mice affects social investigation and aggressive behavior

“…The social paradigm was employed to examine general sociability and cognition in the form of social novelty preference. The test was performed as described (Muhia et al , 2022). A discrimination index used to assess social memory was calculated according to the following formula: Discrimination index = [(TimeNovel – TimeFamiliar)/TimeNovel+Familiar].…”

Skraban‐Deardorff intellectual disability syndrome‐associated mutations in WDR26 impair CTLH E3 complex assembly

“…As such, higher eukaryotes express multiple CTLH E3 assemblies [11,32,34,35]. Indeed, several studies indicate that various CTLH E3 complexes have a range of functions [12,13,36], including cell proliferation, differentiation, and neuronal development [1,30,[37][38][39][40][41][42]. In particular, WDR26 has been associated with a variety of biological processes including G protein-coupled receptor (GPCR) signaling [36,[43][44][45][46][47][48], Wnt signaling [49,50], nuclear condensation, and erythropoiesis [51,52].…”