LRRK2 mutations produce end-stage Parkinson’s disease (PD) with reduced nigrostriatal dopamine, whereas, asymptomatic carriers have increased dopamine turnover and altered brain connectivity. LRRK2 pathophysiology remains unclear, but reduced dopamine and mitochondrial abnormalities occur in aged G2019S mutant knock-in (GKI) mice. Conversely, cultured GKI neurons exhibit increased synaptic transmission. We assessed behavior and synaptic glutamate and dopamine function across a range of ages. Young GKI mice exhibit more vertical exploration, elevated glutamate and dopamine transmission, and aberrant D2-receptor responses. These phenomena decline with age, but are stable in littermates. In young GKI mice, dopamine transients are slower, independent of dopamine transporter (DAT), increasing the lifetime of extracellular dopamine. Slowing of dopamine transients is observed with age in littermates, suggesting premature ageing of dopamine synapses in GKI mice. Thus, GKI mice exhibit early, but declining, synaptic and behavioral phenotypes, making them amenable to investigation of early pathophysiological, and later parkinsonian-like, alterations. This model will prove valuable in efforts to develop neuroprotection for PD.

Mutations in leucine-rich repeat kinase 2 (Lrrk2) are the most common genetic cause of Parkinson's disease (PD), a neurodegenerative disorder affecting 1-2% of those >65 years old. The neurophysiology of LRRK2 remains largely elusive, although protein loss suggests a role in glutamatergic synapse transmission and overexpression studies show altered dopamine release in aged mice. We show that glutamate transmission is unaltered onto striatal projection neurons (SPNs) of adult LRRK2 knockout mice and that adult animals exhibit no detectable cognitive or motor deficits. Basal synaptic transmission is also unaltered in SPNs of LRRK2 overexpressing mice, but they do exhibit clear alterations to D2-receptor-mediated short-term synaptic plasticity, behavioral hypoactivity and impaired recognition memory. These phenomena are associated with decreased striatal dopamine tone and abnormal dopamine- and cAMP-regulated phosphoprotein 32 kDa signal integration. The data suggest that LRRK2 acts at the nexus of dopamine and glutamate signaling in the adult striatum, where it regulates dopamine levels, presynaptic glutamate release via D2-dependent synaptic plasticity and dopamine-receptor signal transduction.

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Palmitoylation of neurotransmitter receptors and associated scaffold proteins regulates their membrane association in a rapid, reversible, and activity-dependent fashion. This makes palmitoylation an attractive candidate as a key regulator of the fast, reversible, and activity-dependent insertion of synaptic proteins required during the induction and expression of long-term plasticity. Here we describe that the constitutive loss of huntingtin interacting protein 14 (Hip14, also known as DHHC17), a single member of the broad palmitoyl acyltransferase (PAT) family, produces marked alterations in synaptic function in varied brain regions and significantly impairs hippocampal memory and synaptic plasticity. The data presented suggest that, even though the substrate pool is overlapping for the 23 known PAT family members, the function of a single PAT has marked effects upon physiology and cognition. Moreover, an improved understanding of the role of PATs in synaptic modification and maintenance highlights a potential strategy for intervention against early cognitive impairments in neurodegenerative disease.almitoylation is a posttranslational protein modification increasingly recognized as an important regulator of neuronal development, synaptic function, and plasticity (1, 2). Palmitoyl acyltransferase (PAT) enzymes regulate membrane association of proteins by catalyzing the addition of the fatty acid palmitate to cysteines via thioester bonds. Palmitoylation is readily reversible, making it an attractive candidate for a regulator of the rapid synaptic protein trafficking required for synaptic transmission and plasticity. The growing list of palmitoylated neuronal substrates includes scaffolds, ion channels, and vesicle-associated proteins, and their palmitoylation status can have dramatic effects on function and/or localization within membranes. For example, synaptic activity dynamically regulates palmitoylation of postsynaptic density protein-95 (PSD-95), influencing its clustering at postsynaptic sites (3-5), whereas palmitoylation of NMDA-and AMPA-type glutamate receptor subunits regulates their insertion, removal, and stabilization in the postsynaptic membrane (6-9). The importance of this modification within the brain is highlighted by implication of palmitoylation deficits in a number of neurological diseases including Alzheimer's disease, schizophrenia, and Huntington disease (HD) (10).To date, 23 DHHC proteins have been identified in humans. The PAT HIP14 (DHHC17) is enriched in the brain and has a number of known synaptic substrates including PSD-95, GluA1/ 2, GAD-65, SNAP-25, and synaptotagmin I (11-13), suggesting roles in pre-and postsynaptic function. Indeed, Hip14 siRNA reduces PSD-95 clustering in hippocampal cultures (12), and Hip14 loss-of-function impairs neurotransmitter release in Drosophila (14). Interestingly, Hip14 function is impaired in HD (15, 16), suggesting that some synaptic deficits observed in this disease (17-23) may arise from hypopalmitoylation of Hip14 substrates. In support of th...

Purpose This study aimed to assess the cardiorespiratory response during a 1-min sit-to-stand test (1STS) in comparison with cycling cardiopulmonary exercise test (CPET) in people with chronic obstructive pulmonary disease (COPD) and in healthy subjects and to evaluate whether 1STS may induce leg fatigue in these individuals. Methods Fourteen people with severe COPD and 12 healthy subjects performed a 1STS and a CPET during which cardiorespiratory response, perception of dyspnea, and leg fatigue were assessed. Quadriceps strength was assessed before and after 1STS, and contractile fatigue was defined as a postexercise fall in quadriceps twitch force greater than 15% of resting values. Results In COPD, peak V˙O2, V˙E, and HR achieved during 1STS reached 113%, 103%, and 93% of the corresponding values during CPET, respectively. Decrease in SpO2 from preexercise to peak exercise and the magnitude of dynamic hyperinflation were similar between 1STS and CPET. Borg dyspnea and leg fatigue scores were higher for CPET than 1STS. In healthy subjects, peak cardiorespiratory demand and symptom scores were higher during CPET compared with 1STS. A V˙O2 overshoot during recovery was observed only in people with COPD. After 1STS, the V˙O2 half-time recovery of COPD was 152 ± 25 s compared with 74 ± 18 in healthy subjects (P < 0.01). Ten people with COPD and five healthy subjects were considered as fatiguers. Conclusion The 1STS induced a similar cardiorespiratory stress to that of CPET and was associated with contractile quadriceps fatigue in people with severe COPD. The V˙O2 overshoot and slower recovery time of cardiorespiratory variables seen in COPD demonstrate the clinical relevance of monitoring the recovery phase of exercise.