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Synucleins are a vertebrate-specific family of abundant neuronal proteins. They comprise three closely related members, [alpha]-, [beta]-, and [gamma]-synuclein. [alpha]-Synuclein has been the focus of intense attention since mutations in it were identified as a cause for familial Parkinson's disease. Despite their disease relevance, the normal physiological function of synucleins has remained elusive. To address this, we generated and characterized [alpha][beta][gamma]-synuclein knockout mice, which lack all members of this protein family. Deletion of synucleins causes alterations in synaptic structure and transmission, age-dependent neuronal dysfunction, as well as diminished survival. Abrogation of synuclein expression decreased excitatory synapse size by ~30% both in vivo and in vitro, revealing that synucleins are important determinants of presynaptic terminal size. Young synuclein null mice show improved basic transmission, whereas older mice show a pronounced decrement. The late onset phenotypes in synuclein null mice were not due to a loss of synapses or neurons but rather reflect specific changes in synaptic protein composition and axonal structure. Our results demonstrate that synucleins contribute importantly to the long-term operation of the nervous system and that alterations in their physiological function could contribute to the development of Parkinson's disease. neurodegeneration | loss-of-function | Lewy bodies | ultrastructure | retina doi/ 10.1073/pnas.1005005107

Transient global or forebrain ischemia induced experimentally in animals can cause selective, delayed neuronal death of hippocampal CA1 pyramidal neurons. A striking feature is a delayed rise in intracellular free [Zn.sup.2+] in CA1 neurons just before the onset of histologically detectable cell death. Here we show that [alpha]-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) at Schaffer collateral to CA1 synapses in postischemic hippocampus exhibit properties of [Ca.sup.2+]/[Zn.sup.2+]-permeable, Glu receptor 2 (GluR2)-lacking AMPARs before the rise in [Zn.sup.2+] and cell death. At 42 h after ischemia, AMPA excitatory postsynaptic currents exhibited pronounced inward rectification and marked sensitivity to 1-naphthyl acetyl spermine (Naspm), a selective channel blocker of GluR2-lacking AMPARs. In control hippocampus, AMPA excitatory postsynaptic currents were electrically linear and relatively insensitive to Naspm. Naspm injected intrahippocampally at 9-40 h after insult greatly reduced the late rise in intracellular free [Zn.sup.2+] in postischemic CA1 neurons and afforded partial protection against ischemia-induced cell death. These results implicate GluR2-lacking AMPA receptors in the ischemia-induced rise in free [Zn.sup.2+] and death of CA1 neurons, although a direct action at the time of the rise in [Zn.sup.2+] is unproven. This receptor subtype appears to be an important therapeutic target for intervention in ischemia-induced neuronal death in humans. glutamate | 1-naphthyl acetyl spermine | neurodegeneration

An abundant presynaptic protein, [alpha]-synuclein, is centrally involved in the pathogenesis of Parkinson's disease. However, conflicting data exist about the normal function of [alpha]-synuclein, possibly because [alpha]-synuclein is redundant with the very similar [beta]-synuclein. To investigate the functions of synucleins systematically, we have now generated single- and double-knockout (KO) mice that lack [alpha]- and/or [beta]-synuclein. We find that deletion of synucleins in mice does not impair basic brain functions or survival. We detected no significant changes in the ultrastructure of synuclein-deficient synapses, in short- or long-term synaptic plasticity, or in the pool size or replenishment of recycling synaptic vesicles. However, protein quantitations revealed that KO of synucleins caused selective changes in two small synaptic signaling proteins, complexins and 14-3-3 proteins. Moreover, we found that dopamine levels in the brains of double-KO but not single-KO mice were decreased by [approximately equal to] 20%. In contrast, serotonin levels were unchanged, and dopamine uptake and release from isolated nerve terminals were normal. These results show that synudeins are not essential components of the basic machinery for neurotransmitter release but may contribute to the long-term regulation and/or maintenance of presynaptic function.

Author(s): Pablo E. Castillo [1, 2, 3]; Susanne Schoch [3, 4]; Frank Schmitz [4, 5]; Thomas C. Südhof [4]; Robert C. Malenka (corresponding author) [1] Two main forms of long-term [...]

Author(s): Susanne Schoch [1, 2]; Pablo E. Castillo [2, 3, 4]; Tobias Jo [5]; Konark Mukherjee [1]; Martin Geppert [5, 6]; Yun Wang [1]; Frank Schmitz [1, 6]; Robert C. [...]

Kainate receptors assembled with the GluR6 subunit are significant for both the sensitivity of CA3 neurons to kainate and for synaptic transmission at the mossy fibre-CA3 synapse, according to research using mutant mice lacking the kainate-receptor subunit GluR6. It was established that GluR6-deficient mice are less susceptible to systemic administration of kainate. This research indicates a vital role for kainate receptors, rather than alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, in kainate-induced seizures and excitoxic neuronal death in the hippocampus.

GABAergic interneurons are highly diverse, and their synaptic outputs express various forms of plasticity. Compelling evidence indicates that activity‐dependent changes of inhibitory synaptic transmission play a significant role in regulating neural circuits critically involved in learning and memory and circuit refinement. Here, we provide an updated overview of inhibitory synaptic plasticity with a focus on the hippocampus and neocortex. To illustrate the diversity of inhibitory interneurons, we discuss the case of two highly divergent interneuron types, parvalbumin‐expressing basket cells and neurogliaform cells, which support unique roles on circuit dynamics. We also present recent progress on the molecular mechanisms underlying long‐term, activity‐dependent plasticity of fast inhibitory transmission. Lastly, we discuss the role of inhibitory synaptic plasticity in neuronal circuits' function. The emerging picture is that inhibitory synaptic transmission in the CNS is extremely diverse, undergoes various mechanistically distinct forms of plasticity and contributes to a much more refined computational role than initially thought. Both the remarkable diversity of inhibitory interneurons and the various forms of plasticity expressed by GABAergic synapses provide an amazingly rich inhibitory repertoire that is central to a variety of complex neural circuit functions, including memory. [ABSTRACT FROM AUTHOR]

The molecular mechanisms and functional significance of endocannabinoids (eCB)-mediated synaptic plasticity in the central nervous system (CNS) with emphasis on long-term plasticity and also the effect of eCB-dependent plasticity in modulating the inducibility of eCB-independent forms of plasticity are examined. The eCB system is emerging as a major player in synaptic plasticity and the list of brain structures and synapses expressing eCB-mediated plasticity might expand with the given wide distribution of CB1 receptors in the CNS.