Neural mechanism underlies CYLD modulation of morphology and synaptic function of medium spiny neurons in dorsolateral striatum

Abstract

Although the deubiquitinase cylindromatosis (CYLD), an abundant protein in the postsynaptic density fraction, plays a crucial role in mediating the synaptic activity of the striatum, the precise molecular mechanism remains largely unclear. Here, using a Cyld-knockout mouse model, we demonstrate that CYLD regulates dorsolateral striatum (DLS) neuronal morphology, firing activity, excitatory synaptic transmission, and plasticity of striatal medium spiny neurons via, likely, interaction with glutamate receptor 1 (GluA1) and glutamate receptor 2 (GluA2), two key subunits of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). CYLD deficiency reduces levels of GluA1 and GluA2 surface protein and increases K63-linked ubiquitination, resulting in functional impairments both in AMPAR-mediated excitatory postsynaptic currents and in AMPAR-dependent long-term depression. The results demonstrate a functional association of CYLD with AMPAR activity, which strengthens our understanding of the role of CYLD in striatal neuronal activity.

Biocytin-Labeling in Whole-Cell Recording: Electrophysiological and Morphological Properties of Pyramidal Neurons in CYLD-Deficient Mice

“…CYLD, which regulates dendritic arbor and spine development in PNs [ 15 ], is highly expressed in the brain [ 32 ]. We have previously shown that CYLD modulates neuronal activity in the PNs of basolateral amygdala (BLA) and in the MSNs of the striatum [ 33 , 34 ] and is critically involved in mediating anxiety-like behavior via activation of striatal microglia [ 35 ]. We next evaluated whether CYLD plays a role in determining the properties of APs and spine morphology in PNs of the M1.…”