Blockade of associative spine enlargement impairs awake cortical function

Awake cortical processing shows distinctive patterns in electroencephalography (EEG), electromyography (EMG), and locomotor activity, reflecting coordinated neural dynamics driven by action potentials and synaptic transmission across wide cortical territories. Although memory processes are consistently engaged during these states, the causal role of associative synaptic plasticity—specifically dendritic-spine enlargement—in sustaining cortical processing and wakefulness has remained unknown, owing to the absence of tools that can selectively abolish 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 after administration of an A/C heterodimeriser, while preserving cellular excitability and NMDA-receptor function. Visual cortical responses were preserved, whereas motor learning in the motor cortex was impaired. With broad frontoparietal expression of SynC, A/C administration induced reversible deficits in goal-directed behaviours, including laser-dot chasing and feeding initiation. It also induced intermittent State-C, a state outside canonical wake and sleep, marked by behavioural arrest with reduced γ-power and a muted rise in slow δ-waves during these episodes. SynC–A/C preserved firing and Ca²⁺ rates but reduced pairwise spike correlations. All effects reversed within ∼1 h. These findings provide direct causal evidence that associative dendritic-spine enlargement sustains cortical processing and wakefulness.