Primary Cilia Loss in Striatal Neurons Disrupts Synaptic Connectivity and Excitatory Transmission and Drives Metabolomic Remodeling

Abstract

Disruption of striatal circuits is a central feature of many neurological and psychiatric disorders, yet the mechanisms that maintain afferent connectivity and synaptic function in striatal neurons remain incompletely defined. Primary cilia are signaling organelles present on almost all striatal medium spiny neurons that are enriched in neuromodulatory receptors, suggesting a role in coordinating striatal neuronal communication and biochemical state. Here, we show that conditional ablation of primary cilia from striatal neurons by AAV-Cre-mediated deletion of Ift88 disrupts the afferent connectivity, synaptic function, and chemical signature of the striatum. Monosynaptic rabies tracing revealed an approximately threefold reduction in brain-wide input convergence onto striatal neurons. Whole-cell recordings showed reduced miniature excitatory postsynaptic current amplitude and frequency together with a reduced NMDA:AMPA ratio, consistent with weakened glutamatergic synaptic transmission. Untargeted metabolomics revealed broad remodeling of the striatal chemical profile, predominantly toward decreased measured levels, with lipid-associated pathways most affected alongside reductions in polyamines, glutamate-related metabolites, and neuromodulatory, particularly excitatory, signaling molecules. By contrast, the cortex, which was not targeted by the AAV injection, showed fewer and directionally opposite molecular changes. These findings identify cilia as essential regulators of the structural, synaptic, and molecular integrity required for normal striatal circuit function.