Mechanisms inducing perforation of the postsynaptic density (PSD) are poorly understood. We show that neural cell adhesion molecule– deficient (NCAM−/−) hippocampal neurons have an abnormally high percentage of synapses with perforated PSDs. The percentage of synapses with perforated PSDs is also increased in wild-type (NCAM+/+) neurons after the disruption of the NCAM/spectrin complex indicating that the NCAM-assembled spectrin cytoskeleton maintains the structural integrity of PSDs. We demonstrate that PSD perforations contain endocytic zones involved in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization. Induction of long-term potentiation in NCAM+/+ neurons accompanied by insertion of AMPAR into the neuronal cell surface is subsequently followed by formation of perforated synapses and AMPAR endocytosis suggesting that perforation of PSDs is important for membrane homeostasis in activated synapses. In NCAM−/− or NCAM+/+ neurons with dissociated spectrin meshwork, AMPAR endocytosis is enhanced under conditions of basal activity. An abnormally high rate of postsynaptic membrane endocytosis may thus contribute to brain pathologies associated with mutations in NCAM or spectrin.
Summary Reliable delivery of presynaptic material, including active zone and synaptic vesicle proteins from neuronal somata to synaptic terminals is prerequisite for faithful synaptogenesis and neurotransmission. However, molecular mechanisms controlling the somatic assembly of presynaptic precursors remain insufficiently understood. Here we show that in mutants of the small GTPase RAB2 active zone and synaptic vesicle proteins accumulated in the neuronal somata at the trans -Golgi network and were consequently depleted at synaptic terminals, provoking neurotransmission deficits. The ectopic presynaptic material accumulations consisted of heterogeneous vesicles and short tubules of 40×60 nm and segregated in subfractions either positive for active zone proteins or co-positive for synaptic vesicle proteins and LAMP1, a lysosomal membrane protein. Genetically, rab2 behaved epistatic over arl8 , a lysosomal adaptor controlling axonal export of precursors. Collectively, we here identified a Golgi-associated assembly sequence in presynaptic precursor vesicle biogenesis controlled by RAB2 dependent membrane remodelling and protein sorting at the trans -Golgi.
In humans, deletions/mutations in the CHL1/CALL gene are associated with mental retardation and schizophrenia. Juvenile CHL1-deficient (CHL1(-/-) ) mice have been shown to display abnormally high numbers of parvalbumin-expressing (PV(+) ) hippocampal interneurons and, as adults, display behavioral traits observed in neuropsychiatric disorders. Here, we addressed the question whether inhibitory interneurons and synaptic plasticity in the CHL1(-/-) mouse are affected during brain maturation and in adulthood. We found that hippocampal, but not neocortical, PV(+) interneurons were reduced with age in CHL1(-/-) mice, from a surplus of +27% at 1 month to a deficit of -20% in adulthood compared with wild-type littermates. This loss occurred during brain maturation, correlating with microgliosis and enhanced interleukin-6 expression. In parallel with the loss of PV(+) interneurons, the inhibitory input to adult CA1 pyramidal cells was reduced and a deficit in short- and long-term potentiation developed at CA3-CA1 excitatory synapses between 2 and 9 months of age in CHL1(-/-) mice. This deficit could be abrogated by a GABAA receptor agonist. We propose that region-specific aberrant GABAergic synaptic connectivity resulting from the mutation and a subsequently enhanced synaptic elimination during brain maturation lead to microgliosis, increase in pro-inflammatory cytokine levels, loss of interneurons, and impaired synaptic plasticity. Close homolog of L1-deficient (CHL1(-/-) ) mice have abnormally high numbers of parvalbumin (PV)-expressing hippocampal interneurons in juvenile animals, but in adult animals a loss of these cells is observed. This loss correlates with an increased density of microglia (M), enhanced interleukin-6 (IL6) production and a deficit in short- and long-term potentiation at CA3-CA1 excitatory synapses. Furthermore, adult CHL1(-/-) mice display behavioral traits similar to those observed in neuropsychiatric disorders of humans.
Abstract Whereas aliphatic aldehydes (II) and ketones with the titanium reagent (I) form the aldol adducts (III) and (IV) in approximately equal erythro/threo ratio, with aromatic and heterocyclic aldehydes (V), α‐alkylidenephenylacetonitriles (VI) are obtained.
Запропоновано модифікацію експериментальної моделі хвороби Паркінсона, що передбачає стереотаксичну інфузію розчину ротенону за допомогою оригінального пристрою у центральну зону компактної частини чорної субстанції (ЧС) дорослих щурів лінії Вістар.Встановлено, що через 10 діб щільність дофамінергічних (ДА) нейронів у ділянці інфузії нейротоксину зменшується майже в 6 разів, до 20,2±3,2 нейронів/мм 2 порівняно з відповідним показником у неушкодженій контралатеральній ЧС, 119,0±3,3 нейронів/мм 2 .Електронна мікроскопія виявила порушення ультраструктури мітохондрій нейронів ЧС у зоні інфузії, що переважно обмежувалися дезорганізацією крист у цих органелах.Відсутність загальної токсичності та селективність ураження тканини мозку свідчать про те, що запропонована модифікація моделі є
This paper addresses spatial aspects of reactive astrogliosis observed in the substantia nigra pars compacta (SNc) in rotenone model of Parkinson's disease.The study was performed on adult male Wistar rats receiving the intracerebral 12 µg rotenone infusion into the left SNc.SNc tissue was analyzed 40, 70 and 200 days after the infusion.It was shown that rotenone caused the increase in astocyte density at all analyzed time-points, thus indicating the proliferation of the cells.Radial distribution function (RDF) analysis demonstrated a non-uniform spatial distribution of nigral astrocytes.Their density was revealed to be higher in the proximity of neuronal cell bodies, especially on the infused side.In addition, RDF analysis provided evidence of spatial clusters of astrocytes 40 days after the infusion.The results of this study suggest that nigral astrogliosis observed in the rotenone model of Parkinson's disease includes changes in spatial distribution of astrocytes.These changes reflect the rearrangement of SNc tissue architecture occurring in response to rotenone-related degeneration of SNc neurons.
