Population signals from neuronal ensembles in cortex during behavior are commonly measured with EEG, local field potential (LFP), and voltage-sensitive dyes. A genetically encoded voltage indicator would be useful for detection of such signals in specific cell types. Here we describe how this goal can be achieved with Butterfly, a voltage-sensitive fluorescent protein (VSFP) with a subthreshold detection range and enhancements designed for voltage imaging from single neurons to brain in vivo. VSFP-Butterfly showed reliable membrane targeting, maximum response gain around standard neuronal resting membrane potential, fast kinetics for single-cell synaptic responses, and a high signal-to-noise ratio. Butterfly reports excitatory postsynaptic potentials (EPSPs) in cortical neurons, whisker-evoked responses in barrel cortex, 25-Hz gamma oscillations in hippocampal slices, and 2- to 12-Hz slow waves during brain state modulation in vivo. Our findings demonstrate that cell class-specific voltage imaging is practical with VSFP-Butterfly, and expand the genetic toolbox for the detection of neuronal population dynamics.

Integrins are a large family of extracellular matrix (ECM) receptors. In the developing and adult brain, many integrins are present at high levels at synapses. The tetrapartite structure of synapses - which comprises presynaptic and postsynaptic neurons, the ECM and glial processes - places synaptic integrins in an excellent position to sense dynamic changes in the synaptic environment and use this information to coordinate further changes in synapse structure and function that will shape neural circuit properties. Recent developments in our understanding of the cellular and physiological roles of integrins, which range from control of neural process outgrowth and synapse formation to regulation of synaptic plasticity and memory, enable us to attempt a synthesis of synaptic integrin function.

Dendrites are neuronal structures specialized for receiving and processing information through their many synaptic inputs. How input strengths are modified across dendrites in ways that are crucial for synaptic integration and plasticity remains unclear. We examined in single hippocampal neurons the mechanism of heterosynaptic interactions and the heterogeneity of synaptic strengths of pyramidal cell inputs. Heterosynaptic presynaptic plasticity that counterbalances input strengths requires N-methyl-D-aspartate receptors (NMDARs) and astrocytes. Importantly, this mechanism is shared with the mechanism for maintaining highly heterogeneous basal presynaptic strengths, which requires astrocyte Ca 2+ signaling involving NMDAR activation, astrocyte membrane depolarization, and L-type Ca 2+ channels. Intracellular infusion of NMDARs or Ca 2+-channel blockers into astrocytes, conditionally ablating the GluN1 NMDAR subunit, or optogenetically hyperpolarizing astrocytes with archaerhodopsin promotes homogenization of convergent presynaptic inputs. Our findings support the presence of an astrocytedependent cellular mechanism that enhances the heterogeneity of presynaptic strengths of convergent connections, which may help boost the computational power of dendrites.synapse heterogeneity | synaptic strength | astrocyte | hippocampal neuron | heterosynaptic plasticity A n enduring challenge in neurobiology is to understand how neurons set the strengths of their numerous synapses to efficiently process and store different information while maintaining network homeostasis. Electrophysiology and imaging approaches have revealed that synapses display a high degree of functional heterogeneity, even for those sharing the same axon or dendrite (1-3). The observation that synaptic strengths are heterogeneous, in turn, suggests that synapses can operate independently from one another. Accordingly, many studies have demonstrated the input-specificity of Hebbian and also of homeostatic forms of synaptic plasticity, where synaptic changes are restricted to inputs whose activity is altered (4-6). Nevertheless, such a synapse-autonomous behavior could potentially compromise the global network homeostasis by biasing the overall activity toward excitation or depression, and to overcome this issue, it has been proposed that distinct inputs cooperate by coordinating their relative strengths through heterosynaptic interactions (7-9). In support of the idea that synapses behave as interdependent rather than isolated functional units, the restriction of synaptic strength changes to active inputs has been demonstrated to break down at times, with the induction of synaptic plasticity in the stimulated input accompanying either synaptic depression or potentiation of the nonstimulated inputs (10-13). In a highly studied plasticity paradigm of long-term potentiation (LTP) at hippocampal Schaffer collateral-CA1 synapses, tetanic stimulation that induces LTP is often accompanied by presynaptic long-term depression (LTD) of nonstimulated Schaffer collat...

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Tyrosinase (EC 1.14.18.1) is a copper-containing monooxygenase enzyme widely distributed in nature, which can be found in fungi, and in higher plants and animals.1) It catalyzes the conversion of tyrosine to dopa, dopaquinone, and subsequent autopolymerization to melanin.2) Tyrosinase inhibitor has been used as a whitening agent or antihyperpigment agent because of its ability to suppress dermal-melanin production. Many scientists are working to isolate tyrosinase inhibitors from natural products. Arbutin, 3) kojic acid, 4) and hydroquinones 5) have been reported to have inhibitory activity. They had been widely used in cosmetic industry as whitening composition. However kojic acid and arbutin have been failed to demonstrate the inhibitory activity of pigmentation in intact melanocytes or in clinical trial.6) Hydroquinones are considered to be cytotoxic to melanocytes and potentially mutagenic to mammalian cells. 6) Since the most widely used compounds failed to demonstrate the clinical efficacy, there is a strong need to develop a new tyrosinase inhibitor that is clinically active.Aloe (Liliaceae) is a perennial evergreen, herbaceous plant or tropical woody plant. More than 360 species are known in the world. It has long-been used in folk medicine for the treatment of burns and dermatitis. It is also widely used in the cosmetic industry as a moisturizing agent and skinwhitening composition. Recently aloesin (1) was reported as a tyrosinase-inhibitory principle to this plant, [7][8][9] and it is now used as a whitening composition in cosmetics. Recently one of Korean research group demonstrated clinical efficacy of aloesin.10) Currently, aloesin is purified from aloe, however this purification method involves a complex and time-consuming process. Aloesin is difficult to synthesize due to its C-glycosyl moiety.In this study, we attempted to locate a tyrosinase inhibitory chromone compound which possess more potent tyrosinaseinhibitory activity than aloesin, and which is easier to synthesize. Results and DiscussionAloesin is difficult to synthesize because of the C-glycosyl moiety in the molecule. Since the purpose of this study was to search for a new compound that is easy to synthesize, our first goal centered around whether or not a chromone skeleton without C-glycoside has tyrosinase inhibition activity. Consequently, we synthesized compound 2 that has no C-glycosyl moiety, and then we evaluated its activity. Fortunately, compound 2 exhibited stronger inhibition activity (IC 50 ϭ 0.75 mM) than aloesin (1) itself (IC 50 ϭ0.90 mM).Our next concern was the alkylation of hydroxyl group at the 7-C-position. The protection and deprotection process of hydroxyl group at the 7-C-position in the synthetic pathway of 2, reduced the overall yield. Therefore, alkylation of hydroxyl group at the 7-C-position is beneficial since the deprotection process is unnecessary. We synthesized C 1 -C 4 alkyl ether derivatives (compounds 3-9), and their activity was examined. The longer alkyl group showed weaker inhibition activity. Fo...