Blockade of associative spine enlargement impairs awake cortical function

Awake cortical processing exhibits characteristic signatures in electroencephalography (EEG), electromyography (EMG), and locomotor activity, reflecting coordinated neural network dynamics driven by action potentials and synaptic transmission across broad cortical areas. Although memory functions are commonly engaged during these states, the causal contribution of associative synaptic plasticity, such as dendritic-spine enlargement, to ongoing cortical processing and wakefulness has remained unresolved, largely due to the lack of tools to selectively eliminate spine enlargement in vivo. Here we show that a Rac1-GAP based variant of Synaptic Chemogenetics (SYNCit-C, SynC), selectively and reversibly abolishes spine enlargement following administration of an A/C heterodimeriser, while leaving cellular excitability and NMDA-receptor function intact. Visual cortical responses were preserved, whereas motor learning was impaired in motor cortex. With broad frontoparietal SynC expression, A/C induced reversible deficits in goal-directed behaviours (laser-dot chasing and feeding initiation). It also caused intermittent State-C, a state outside canonical wake and sleep, marked by behavioural arrest and during these episodes, reduced gamma power and a blunted slow delta wave rise. SynC-A/C preserved firing and Ca rates, while pairwise spike correlations were reduced. All effects were reversible within ~1 h. These findings provide causal evidence that associative dendritic-spine enlargement supports awake cortical processing and wakefulness.