Elevated synaptic vesicle release probability in synaptophysin/gyrin family quadruple knockouts

Synaptophysins 1 and 2 and synaptogyrins 1 and 3 constitute a major family of synaptic vesicle membrane proteins. Unlike other widely expressed synaptic vesicle proteins such as vSNAREs and synaptotagmins, the primary function has not been resolved. Here, we report robust elevation in the probability of release of readily releasable vesicles with both high and low release probabilities at a variety of synapse types from knockout mice missing all four family members. Neither the number of readily releasable vesicles, nor the timing of recruitment to the readily releasable pool was affected. The results suggest that family members serve as negative regulators of neurotransmission, acting directly at the level of exocytosis to dampen connection strength selectively when presynaptic action potentials fire at low frequency. The widespread expression suggests that chemical synapses may play a frequency filtering role in biological computation that is more elemental than presently envisioned

RNAi-Based GIuN3A Silencing Prevents and Reverses Disease Phenotypes Induced by Mutant huntingtin

Huntington’s disease (HD) is a dominantly inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. HD symptoms include severe motor, cognitive, and psychiatric impairments that result from dysfunction and later degeneration of medium-sized spiny neurons (MSNs) in the striatum. A key early pathogenic mechanism is dysregulated synaptic transmission due to enhanced surface expression of juvenile NMDA-type glutamate receptors containing GluN3A subunits, which trigger the aberrant pruning of synapses formed by cortical afferents onto MSNs. Here, we tested the therapeutic potential of silencing GluN3A expression in YAC128 mice, a well-established HD model. Recombinant adeno-associated viruses encoding a short-hairpin RNA against GluN3A (rAAV-shGluN3A) were generated, and the ability of different serotypes to transduce MSNs was compared. A single injection of rAAV9-shGluN3A into the striatum of 1-month-old mice drove potent (>90%) and long-lasting reductions of GluN3A expression in MSNs, prevented dendritic spine loss and improved motor performance in YAC128 mice. Later delivery, when spine pathology is already apparent, was also effective. Our data provide proof-of-concept for GluN3A silencing as a beneficial strategy to prevent or reverse corticostriatal disconnectivity and motor impairment in HD and support the use of RNAi-based or small-molecule approaches for harnessing this therapeutic potential

Phenylbutyrate rescues dendritic spine loss associated with memory déficits in a Mouse modelo f Alzheimer´s disease

Alzheimer’s disease (AD) and ageing are associated with impaired learning and memory, and recent findings point toward modulating chromatin remodeling through histone acetylation as a promising therapeutic strategy. Here we report that systemic administration of the HDAC inhibitor 4-phenylbutyrate (PBA) reinstated fear learning in the Tg2576 mouse model of AD. Tg2576 mice develop age-dependent amyloid pathology and cognitive decline that closely mimics disease progression in humans. Memory reinstatement by PBA was observed independently of the disease stage: both in 6-month-old Tg2576 mice, at the onset of the first symptoms, but also in aged, 12- to 16-month-old mice, when amyloid plaque deposition and major synaptic loss has occurred. Reversal of learning deficits was associated to a PBA-induced clearance of intraneuronal Ab accumulation, which was accompanied by mitigation of endoplasmic reticulum (ER) stress, and to restoration of dendritic spine densities of hippocampal CA1 pyramidal neurons to control levels. Furthermore, the expression of plasticity-related proteins such as the NMDA receptor subunit NR2B and the synaptic scaffold SAP102 was significantly increased by PBA. Our data suggest that the beneficial effects of PBA in memory are mediated both via its chemical chaperone- like activity and via the transcriptional activation of a cluster of proteins required for the induction of synaptic plasticity and structural remodeling

Phenylbutyrate rescues dendritic spine loss associated with memory déficits in a Mouse modelo f Alzheimer´s disease

Alzheimer’s disease (AD) and ageing are associated with impaired learning and memory, and recent findings point toward modulating chromatin remodeling through histone acetylation as a promising therapeutic strategy. Here we report that systemic administration of the HDAC inhibitor 4-phenylbutyrate (PBA) reinstated fear learning in the Tg2576 mouse model of AD. Tg2576 mice develop age-dependent amyloid pathology and cognitive decline that closely mimics disease progression in humans. Memory reinstatement by PBA was observed independently of the disease stage: both in 6-month-old Tg2576 mice, at the onset of the first symptoms, but also in aged, 12- to 16-month-old mice, when amyloid plaque deposition and major synaptic loss has occurred. Reversal of learning deficits was associated to a PBA-induced clearance of intraneuronal Ab accumulation, which was accompanied by mitigation of endoplasmic reticulum (ER) stress, and to restoration of dendritic spine densities of hippocampal CA1 pyramidal neurons to control levels. Furthermore, the expression of plasticity-related proteins such as the NMDA receptor subunit NR2B and the synaptic scaffold SAP102 was significantly increased by PBA. Our data suggest that the beneficial effects of PBA in memory are mediated both via its chemical chaperone- like activity and via the transcriptional activation of a cluster of proteins required for the induction of synaptic plasticity and structural remodeling

Sparse force‑bearing bridges between neighboring synaptic vesicles

Most vesicles in the interior of synaptic terminals are clustered in clouds close to active zone regions of the plasma membrane where exocytosis occurs. Electron-dense structures, termed bridges, have been reported between a small minority of pairs of neighboring vesicles within the clouds. Synapsin proteins have been implicated previously, but the existence of the bridges as stable structures in vivo has been questioned. Here we use electron tomography to show that the bridges are present but less frequent in synapsin knockouts compared to wildtype. An analysis of distances between neighbors in wildtype tomograms indicated that the bridges are strong enough to resist centrifugal forces likely induced by fxation with aldehydes. The results confrm that the bridges are stable structures and that synapsin proteins are involved in formation or stabilization

Elevated synaptic vesicle release probability in synaptophysin/gyrin family quadruple knockouts

Synaptophysins 1 and 2 and synaptogyrins 1 and 3 constitute a major family of synaptic vesicle membrane proteins. Unlike other widely expressed synaptic vesicle proteins such as vSNAREs and synaptotagmins, the primary function has not been resolved. Here, we report robust elevation in the probability of release of readily releasable vesicles with both high and low release probabilities at a variety of synapse types from knockout mice missing all four family members. Neither the number of readily releasable vesicles, nor the timing of recruitment to the readily releasable pool was affected. The results suggest that family members serve as negative regulators of neurotransmission, acting directly at the level of exocytosis to dampen connection strength selectively when presynaptic action potentials fire at low frequency. The widespread expression suggests that chemical synapses may play a frequency filtering role in biological computation that is more elemental than presently envisioned