Novelty-seeking behaviors and impulsivity are personality traits associated with several psychiatric illnesses including attention deficits hyperactivity disorders. The underlying neural mechanisms remain poorly understood. We produced and characterized a line of knockout mice for zdhhc15, which encodes a neural palmitoyltransferase. Genetic defects of zdhhc15 were implicated in intellectual disability and behavioral anomalies in humans. Zdhhc15-KO mice showed normal spatial learning and working memory but exhibited a significant increase in novelty-induced locomotion in open field. Striatal dopamine content was reduced but extracellular dopamine levels were increased during the habituation phase to a novel environment. Administration of amphetamine and methylphenidate resulted in a significant increase in locomotion and extracellular dopamine levels in the ventral striatum of mutant mice compared to controls. Number and projections of dopaminergic neurons in the nigrostriatal and mesolimbic pathways were normal. No significant change in the basal palmitoylation of known ZDHHC15 substrates including DAT was detected in striatum of zdhhc15 KO mice using an acyl-biotin exchange assay. These results support that a transient, reversible, and novelty-induced elevation of extracellular dopamine in ventral striatum contributes to novelty-seeking behaviors in rodents and implicate ZDHHC15-mediated palmitoylation as a novel regulatory mechanism of dopamine in the striatum.

The relationship between Parkinson’s disease (PD), the second-most common neurodegenerative disease after Alzheimer’s disease, and palmitoylation, a post-translational lipid modification, is not well understood. In this study, to better understand the role of protein palmitoylation in PD and the pathways altered in this disease, we analyzed the differential palmitoyl proteome (palmitome) in the cerebral cortex of PD patients compared to controls (n = 4 per group). Data-mining of the cortical palmitome from PD patients and controls allowed us to: (i) detect a set of 150 proteins with altered palmitoylation in PD subjects in comparison with controls; (ii) describe the biological pathways and targets predicted to be altered by these palmitoylation changes; and (iii) depict the overlap between the differential palmitome identified in our study with protein interactomes of the PD-linked proteins α-synuclein, LRRK2, DJ-1, PINK1, GBA and UCHL1. In summary, we partially characterized the altered palmitome in the cortex of PD patients, which is predicted to impact cytoskeleton, mitochondrial and fibrinogen functions, as well as cell survival. Our study suggests that protein palmitoylation could have a role in the pathophysiology of PD, and that comprehensive palmitoyl-proteomics offers a powerful approach for elucidating novel cellular pathways modulated in this neurodegenerative disease.

Vesicles within presynaptic terminals are thought to be segregated into a variety of readily releasable and reserve pools. The nature of the pools and trafficking between them is not well understood, but pools that are slow to mobilize when synapses are active are usually assumed to feed pools that are mobilized more quickly, in a series. However, results from electrophysiological studies of synaptic transmission suggested instead a parallel organization where vesicles within slowly and quickly mobilized reserve pools would separately feed independent reluctant- and fast-releasing subdivisions of the readily releasable pool, without intermixing. We now use FM-dyes to confirm the existence of multiple reserve pools at hippocampal synapses. We then confirm the prediction that slowly and quickly mobilized reserve pools do not intermix, even when mobilized by high frequency stimulation. The result provides a simplifying new constraint on the dynamics of vesicle recycling within presynaptic terminals. The experiments additionally demonstrated extensive heterogeneity among synapses in the relative sizes of slowly and quickly mobilized reserve pools. The heterogeneity suggests equivalent heterogeneity in the probability of release among readily releasable vesicles that may be relevant for understanding information processing and storage.

Vesicles within presynaptic terminals are thought to be segregated into a variety of readily releasable and reserve pools. The nature of the pools and trafficking between them is not well understood, but pools that are slow to mobilize when synapses are active are usually assumed to feed pools that are mobilized more quickly, in a series. However, results from electrophysiological studies of synaptic transmission suggested instead a parallel organization where vesicles within slowly and quickly mobilized reserve pools would separately feed independent reluctant- and fast-releasing subdivisions of the readily releasable pool, without intermixing. We now use FM-dyes to confirm the existence of multiple reserve pools at hippocampal synapses. We then confirm the prediction that slowly and quickly mobilized reserve pools do not intermix, even when mobilized by high frequency stimulation. The result provides a simplifying new constraint on the dynamics of vesicle recycling within presynaptic terminals. The experiments additionally demonstrated extensive heterogeneity among synapses in the relative sizes of slowly and quickly mobilized reserve pools. The heterogeneity suggests equivalent heterogeneity in the probability of release among readily releasable vesicles that may be relevant for understanding information processing and storage.