Biology subjects

Ackermann, F.

Publications and source records attributed to Ackermann, F..

3 recordsLinked to original sources

bioRxiv2018

Light induced synaptic vesicle autophagy

The regulated turnover of synaptic vesicle (SV) proteins is thought to involve the ubiquitin dependent tagging and degradation through endo-lysosomal and autophagy pathways. Yet, it remains unclear which of these pathways are used, when they become activated and whether SVs are cleared en-mass together with SV proteins or whether both are degraded selectively. Equally puzzling is how quickly these systems can be activated and whether they function in real time to support synaptic health. To address these questions, we have developed an imaging based system that simultaneously tags presynaptic proteins while monitoring autophagy. Moreover, by tagging SV proteins with a light activated reactive oxygen species (ROS) generator, Supernova, it was possible to temporally control the damage to specific SV proteins and assess their consequence to autophagy mediated clearance mechanisms and synaptic function. Our results show that, in mouse hippocampal neurons, presynaptic autophagy can be induced in as little as 5-10 minutes and eliminates primarily the damaged protein rather than the SV en-mass. Importantly, we also find that autophagy is essential for synaptic function, as light-induced damage to e.g. Synaptophysin only compromises synaptic function when autophagy is simultaneously blocked. These data support the concept that presynaptic boutons have a robust highly regulated clearance system to maintain not only synapse integrity, but also synaptic function.

neuroscience↗

bioRxiv2018

Mutant Screen Reveals the Piccolo’s Control over Depression and Brain-Gonad Crosstalk

Successful sexual reproduction involves complex, genetically encoded interplay between animal physiology and behavior. The rat provides a highly fecund mammalian model for studying how the brain impacts reproduction. Here, we report a forward genetics screen in rats to identify genes that affect reproduction. A panel of 18 distinct rat strains harboring Sleeping Beauty gene trap mutations were analyzed for the ability to reproduce. As expected, our mutant screen identified genes where reproductive failure was connected to gametogenesis (Btrc, Pan3, Spaca6, Ube2k) and embryogenesis (Alk3, Exoc6b, Slc1a3, Tmx4, Zmynd8). In addition, we identified Ata13 (longevity) and Pclo (neuronal disorders), previously not associated with an inability to conceive. Neurologically, Pclo is known to regulate the size of presynaptic vesicle pools. Here, dominant traits in Pclo mutant rats caused epileptiform activity and affected genes supporting GABAergic synaptic transmission (Gabra6, Gabrg3). Recessive traits in Pclo mutant rats transmitted altered reproductive behavior, as homozygous Pclo mutant rats produced gametes but neither sex would mate with wildtype rats. Pclo mutant rat behavior was linked to endophenotypes signifying compromised brain-gonad crosstalk via disturbed GnRH signaling and allelic markers for major depressive disorder in humans (Grm5, Htr2a, Sorcs3, Negr1, Drd2). Thus, by rat genetics, we identified Pclo as a candidate presynaptic factor required for reproduction. Author SummaryPiccolo gene mutations have previously been identified in human cohorts diagnosed with behavioral syndromes that impact ones emotions, including depression and bipolar disorder. Although studies in human populations implicate changes to Piccolos DNA sequence to enhanced susceptibility for behavioral disorders, studies in mouse models have yet to link Piccolo mutations to altered behavior. Here, by a novel genetics approach, we report Piccolo mutation-dependent effects on reproductive behavior in rats, a finding that may turn out to be relevant to the behavioral effects that are associated with human Piccolo gene mutations. Thus, research aimed at understanding how Piccolo functions to regulate reproduction in rats could prove pivotal in our ability to understand neurological mechanisms that influence human emotions.

genetics↗

bioRxiv2018

Critical role for Piccolo in Synaptic Vesicle Retrieval

Loss of function of the presynaptic active zone protein Piccolo has recently been linked to a devastating disease causing brain atrophy. Here, we address how Piccolo inactivation adversely affects synaptic function and thus may contributes to neuronal loss. Our analysis shows that Piccolo is critical for the activity dependent recycling and maintenance of synaptic vesicles (SVs). Specifically, we find that boutons lacking Piccolo have deficits in the Rab5/EEA1 dependent formation of early endosomes and thus the recycling of SVs. Mechanistically, impaired Rab5 function was caused by the reduced synaptic recruitment of Pra1, known to interact selectively with the zinc fingers of Piccolo. Importantly, over-expression of GTPase deficient Rab5 or the Znf1 domain of Piccolo restores the size and recycling of SV pools. These data provide a molecular link between the active zone and endosome sorting at synapses providing hints to how Piccolo contributes to both developmental and psychiatric disorders.\n\nImpact StatementThe efficient recycling of synaptic vesicle proteins is critical for the integrity and reliability of synaptic transmission. Increasingly genetic and environmental insults have been shown to affect this recycling pathway, resulting in both cognitive impairment in humans and neurodegenerative diseases, yet the underlying mechanisms are poorly understood. Here we could show that the presynaptic active zone protein Piccolo regulates efficient recycling of synaptic vesicles via Pra1 and Rab5, perhaps explaining why Piccolo loss of function contributes to Pontocerebellar Hypoplasia and major depressive disorders.

neuroscience↗