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hypersensitivity system, an in vivo 2. Sun, J.C., Beilke, J.N., and Lanier, L.L. (2009). to parental marrow grafts in adult F1 hybrid Adaptive immune features of natural killer cells. mice. Nature 204, 450–453. reaction that involves poorly defined Nature 457, 557–561. 11. Glas, R., Franksson, L., Une, C., Eloranta, M.L., haptenated cell surface ‘antigens’, is 3. Cooper, M.A., Elliott, J.M., Keyel, P.A., Yang, L., Ohlen, C., Orn, A., and Karre, K. (2000). not ideal for defining novel recognition Carrero, J.A., and Yokoyama, W.M. (2009). Recruitment and activation of natural killer (NK) Cytokine-induced memory-like natural killer cells in vivo determined by the target receptors. cells. Proc. Natl. Acad. Sci. USA 106, cell phenotype: An adaptive component of NK The new data mark an evolution 1915–1919. cell-mediated responses. J. Exp. Med. 191, 4. Raulet, D.H. (2004). Interplay of natural killer 129–138. from the view that NK cells respond cells and their receptors with the adaptive 12. Gidlund, M., Orn, A., Wigzell, H., Senik, A., and de novo to each insult. The sustained immune response. Nat. Immunol. 5, Gresser, I. (1978). Enhanced NK cell activity in sensitization of NK cells as a result of 996–1002. mice injected with interferon and interferon 5. Dorshkind, K., Pollack, S.B., Bosma, M.J., and inducers. Nature 273, 759. cytokines or infection at the least Phillips, R.A. (1985). Natural killer (NK) cells are 13. Carson, W.E., Giri, J.G., Lindemann, M.J., constitutes a form of hazy, fairly present in mice with severe combined Linett, M.L., Ahdieh, M., Paxton, R., immunodeficiency (scid). J. Immunol. 134, Anderson, D., Eisenmann, J., Grabstein, K., short-term memory, wherein a previous 3798–3801. and Caligiuri, M.A. (1994). Interleukin (IL) 15 encounter ensures that NK cells will, 6. Lanier, L.L. (2008). Up on the tightrope: natural is a novel cytokine that activates human for a period of weeks or months, lash killer cell activation and inhibition. Nat. natural killer cells via components of the Immunol. 9, 495–502. IL-2 receptor. J. Exp. Med. 180, out vigorously when exposed to the 7. Murali-Krishna, K., Altman, J.D., Suresh, M., 1395–1403. same or a different insult. The clonal Sourdive, D., Zajac, A., Miller, J., Slansky, J., and 14. O’Leary, J.G., Goodarzi, M., Drayton, D.L., Ahmed, R. (1998). Counting antigen-specific and von Andrian, U.H. (2006). T cell- and expansion data and contact CD8 T cells: a reevaluation of bystander B cell-independent adaptive immunity hypersensitivity data indicate that more activation during viral infection. Immunity 8, mediated by natural killer cells. Nat. specific NK cell memories exist as well, 177–187. Immunol. 7, 507–516. 8. Kaech, S.M., Wherry, E.J., and Ahmed, R. but a detailed understanding of how (2002). Effector and memory T-cell this works, and how important it is, differentiation: implications for vaccine Department of Molecular and Cell development. Nat. Rev. Immunol. 2, Biology and Cancer Research Laboratory, awaits data that clarify whether novel 251–262. 489 Life Sciences Addition, University NK cell receptors, or specificities, exist. 9. Dokun, A.O., Kim, S., Smith, H.R., Kang, H.S., of California at Berkeley, Berkeley, Chu, D.T., and Yokoyama, W.M. (2001). CA 94720, USA. Specific and nonspecific NK cell activation References during virus infection. Nat. Immunol. 2, E-mail: [email protected] 1. Medzhitov, R. (2007). Recognition of 951–956. microorganisms and activation of the immune 10. Cudkowicz, G., and Stimpfling, J.H. (1964). response. Nature 449, 819–826. Induction of immunity and of unresponsiveness DOI: 10.1016/j.cub.2009.02.023

Synaptic Transmission: Excitatory sustained activation of certain Aplysia during feeding behavior may Autapses Find a Function? be aided by excitatory autapses. In this context, then, an excitatory autapse makes perfect sense: autaptic An autapse is a between a and itself, a peculiar structure with self-excitation tips the neuron into an unclear function. A new study suggests that excitatory autapses contribute a hyperexcitable state that requires the to a positive-feedback loop that maintains persistent electrical activity in persistent firing of action potentials. neurons. Saada et al. [7] studied the buccal ganglia of Aplysia, focusing on John M. Bekkers Finallly, neurotransmission might B31/B32 neurons, motor neurons that occur at autapses. drive muscles involved in grasping Although the brain is complicated, An autapse is a self-synapse, food during a repetitive feeding we are told in undergraduate biology a specialized structure in which behavior in these animals [8]. When classes that the basic circuit element a neuron forms a synaptic connection briefly stimulated in intact ganglia, is simple: the of one neuron between its axon and its own B31/B32 neurons exhibit a prolonged forms on the dendrites of [4,5]. Anatomical autapses are not depolarization and firing of action another neuron, and information is uncommon in neural circuits, but potentials (Figure 1), producing conveyed from cell to cell like the their purpose has remained puzzling. sustained muscle contraction. The baton in a relay race. The reality is, Inhibitory autapses — those made authors wished to understand the of course, more complex. The brain by a neuron that releases an inhibitory mechanism of the persistent activity has evolved other avenues of neurotransmitter such as g-amino- in B31/B32 cells. communication that seem to lack the butyric acid (GABA) — seem to make These cells are embedded in sequential, neuron-to-neuron sense because they could provide a surprisingly complex circuit discipline of synaptic transmission. a self-stabilizing influence (‘negative (Figure 1). They receive both fast For example, neurotransmitter might feedback’) [6]. But what about and slow excitatory synaptic inputs spill out of the synaptic cleft and excitatory autapses? Why should mediated by release of acetylcholine activate receptors on nearby neurons, a neuron want to destabilize itself by from presynaptic neurons, the B63 including the neuron that released the self-excitation in a positive-feedback cells. In addition, they are electrically transmitter [1,2]. Crosstalk could also loop? In a recent issue of Current connected to B63 cells via gap occur between neurons and Biology, Saada et al. [7] propose an junctions. These connections make it non-neuronal cells, such as [3]. answer to this question: that the difficult to establish with certainty the Dispatch R297 existence of a postulated excitatory autapse in a B31/B32 neuron (red in B31/B32 cell B31/B32 autapse Figure 1). If an action potential occurs starts firing is active in the B31/B32 cell it could pass through the into the B63 cell, exciting it to cause normal synaptic transmitter release. Such a response would look just like EPSPs from an autapse: an action potential in B63 cell the B31/B32 neuron produces a 10 mV postsynaptic potential in the same cell. One would be fooled into 1 sec thinking an autapse is present when it is not. Saada et al. [7] elegantly resolved Increasing this ambiguity by simultaneously Stimulate depolarization recording from the and axon of a B31/B32 neuron. By stimulating the axon directly, they were able to show that a slow, muscarinic synaptic (or autaptic) response could be recorded in the B31/B32 neuron, even when the B63 synapse was clearly silent. Hence, B63 B31/B32 they tentatively concluded that Muscle B31/B32 cells do possess autapses, and they release acetylcholine onto themselves to produce a slow, muscarinic excitation that aids persistent activity. Next, Saada et al. [7] turned to a simplified culture system in which Current Biology they were able to demonstrate the presence of autaptic connections in Figure 1. Electrical activity in a B31/B32 neuron in an intact (top), and the postulated an isolated B31/B32 neuron, without circuit that gives rise to this behavior (bottom). the complications of the intact Following brief electrical stimulation to either the B63 or B31/B32 neuron, excitatory post- ganglion. This is a risky strategy. synaptic potentials (EPSPs), due to the release of acetylcholine from the B63 cell, are observed Mammalian neurons that do not form in the B31/B32 cell. These EPSPs accelerate and merge, causing increasing depolarization. autapses in vivo commonly establish Eventually the B31/B32 cell starts firing action potentials, which activates the slow, muscarinic profuse autaptic connections B31/B32 autapse (red connection, bottom panel). Synaptic release from the B63 cell can also occur due to electrical coupling between the B31/B32 cell and the B63 axon (zigzag line). when they are grown in cell culture, Repolarization is produced by inhibitory inputs that are not shown in this figure. presumably as an adaptation to the lack of axonal guidance cues [4,9]. Thus, the presence of autapses in vitro has shown are unlikely to contact Indeed, Saada et al. [7] suggest, by no means confirms their presence other neurons in the ganglion, may somewhat paradoxically, that the in vivo. Nevertheless, the authors be the sites of autaptic release of autapse might be more important for found that isolated B31/B32 neurons in acetylcholine. Strictly speaking, these turning off the sustained activity culture did form autaptic connections data are insufficient to formally define than maintaining it. This and other with properties similar to those seen an autapse, which is a structural questions could be resolved by in the intact ganglion. Importantly, specialization that is indistinguishable, finding a way to selectively block they also showed that some other at the ultrastructural level, from the autaptic input in the intact ganglion types of buccal ganglion neurons a synapse [10,11]. The possibility and measuring the effect of its that did not form autapses in situ also remains that the boutons on B31/B32 absence. did not form them in culture. In other simply release acetylcholine This paper [7] is significant because words, unlike mammalian neurons, into the , giving rise to a slow, it provides the first evidence of Aplysia neurons seem to retain their autocrine response. If so, this would a function for excitatory autapses synaptic phenotype when placed in not be a true autapse. Electron (or autapse-like structures) in an cell culture. This encourages microscopy would be necessary intact neural circuit. It is also confidence in the validity of the test. to resolve this uncertainty. satisfying that these autapses are Finally, Saada et al. [7] used The paper [7] also provokes other present in exactly the kind of circuit fluorescence microscopy to show the questions. For example, it is unclear where one would expect to find presence of putative boutons on the how much of the sustained activity them: a positive-feedback loop in axon of B31/B32 neurons close to is due to the autapse and how much which electrical activity must be the cell soma. They suggest that to other circuit elements, notably the sustained for several seconds in these boutons, which other evidence strong synaptic input from B63 cells. order to effect a behavior [8]. These Current Biology Vol 19 No 7 R298

findings suggest that excitatory 5. Bekkers, J.M. (2003). Synaptic transmission: 10. Lu¨bke, J., Markram, H., Frotscher, M., and Functional autapses in the cortex. Curr. Biol. Sakmann, B. (1996). Frequency and autapses, like their inhibitory cousins, 13, R433–R435. dendritic distribution of autapses may well have evolved to fulfil a 6. Bacci, A., Huguenard, J.R., and Prince, D.A. established by Layer 5 pyramidal neurons in legitimate role in all kinds of nervous (2003). Functional autaptic neurotransmission the developing rat : Comparison in fast-spiking : A novel form of with synaptic innervation of adjacent systems. feedback inhibition in the neocortex. neurons of the same class. J. Neurosci. J. Neurosci. 23, 859–866. 16, 3209–3218. 7. Saada, R., Miller, N., Hurwitz, I., and 11. Tama´ s, G., Buhl, E.H., and Somogyi, P. (1997). References Susswein, A.J. (2009). Autaptic muscarinic Massive autaptic self-innervation of GABAergic 1. Bacci, A., Huguenard, J.R., and Prince, D.A. excitation underlies a plateau potential and neurons in cat visual cortex. J. Neurosci. 17, (2004). Long-lasting self-inhibition of persistent activity in a neuron of known 6352–6364. neocortical interneurons mediated by behavioral function. Curr. Biol. 19, 479–484. endocannabinoids. Nature 431, 312–316. 8. Hurwitz, I., Cropper, E.C., Vilim, F.S., 2. Rusakov, D.A., Kullmann, D.M., and Alexeeva, V., Susswein, A.J., Kupfermann, I., John Curtin School of Medical Research, The Stewart, M.G. (1999). Hippocampal synapses: and Weiss, K.R. (2000). Serotonergic and Australian National University, Canberra, ACT do they talk to their neighbours? Trends peptidergic modulation of the buccal mass 0200, Australia. Neurosci. 22, 382–388. protractor muscle (I2) in Aplysia.J. 3. Auld, D.S., and Robitaille, R. (2003). Glial cells Neurophysiol. 84, 2810–2820. E-mail: [email protected] and neurotransmission: An inclusive view of 9. Craig, A.M., and Boudin, H. (2001). Molecular synaptic function. Neuron 40, 389–400. heterogeneity of central synapses: afferent 4. Ikeda, K., and Bekkers, J.M. (2006). Autapses. and target regulation. Nat. Neurosci. 4, Curr. Biol. 16, R308. 569–578. DOI: 10.1016/j.cub.2009.02.010

Circadian Biology: An Unexpected rhythmic synthesis of transcriptional repressors could result in the cyclic Invitee to New Time Zones transcription of genes controlled by activators that are targets of the repressors [14]. The data presented Adaptation to changing light conditions is a hallmark of the circadian clock. by Duffield and colleagues [8] seem A new study points to the critical role played by a transcriptional repressor to fall into this regulatory scenario. previously implicated in cell differentiation, highlighting unappreciated links Indeed, Id2 has a repressive effect between the clock and the control of development and tumorigenesis. on CLOCK–BMAL1-mediated transactivation of a clock promoter, Satoru Masubuchi in this equation — Id2 (inhibitor of suggesting that Id2 could and Paolo Sassone-Corsi* DNA-binding gene 2), a transcriptional physiologically participate in repressor that controls bHLH regulating the clock machinery. Flying from Europe to California activators that, like CLOCK and Although direct molecular interaction imposes on travelers an almost full BMAL1, regulate genes with E-box between Id2 and components of the reversal of the light–dark regime, promoter elements. The first studies of circadian clock was not formally a drastic event that forces the circadian the Id gene showed that it encoded an demonstrated, the results suggest an clock to reset its gears in order to inhibitor of the muscle-differentiation- unexpected example of a regulatory adjust to the new cycle. Resetting inducing transcription factor MyoD [9], cross-talk, in which the mechanism occurs through alterations in the and a group of similar genes was of the clock would be controlled by molecular machinery that constitutes subsequently identified [10]. All Id a non-canonical clock transcription the clock [1,2], a system that basically proteins have a HLH domain but lack factor. operates in each cell of our body [3]. a DNA-binding domain, thereby acting How is Id2 involved in the circadian Several studies have documented as transcriptional repressors by simply rhythm? The authors exposed Id2-null a correlation between repeated jet sequestering the activators by mice to a time-zone change in the lag and a number of pathological heterodimerization [10]. For years, light–dark cycle, a procedure that conditions, including metabolic studies have focused on the function mimics jet lag. Wild-type mice normally disorders, insomnia, cognitive deficits of Id proteins in early development, in require four or five days to fully adjust and cancer [4–7]. Experiments reported the context of specific differentiation to a ten-hour shift (humans need in a recent issue of Current Biology by programs or in cancer [10]. Little was virtually an equivalent adjusting Duffield et al. [8] may provide a clue as known, however, regarding their period), whereas the mutant mice to the molecular mechanisms behind possible physiological role in adult life, took only one or two days to recover these observations. so the reported interplay with the clock from the ‘jet lag’ (Figure 1). Thus, it The molecular organization of the system constitutes a surprising and would seem that Id2 operates as circadian clock is based on interlocking revealing twist. a modulator of the adaptation to light, positive and negative transcriptional– A first hint of the involvement of one of the key features of the circadian translational feedback loops, in which Id genes in circadian regulation was clock. Intriguingly, a very similar jet lag a heterodimer comprising the basic their oscillatory expression, observed phenotype has been observed in helix-loop-helix (bHLH) transcription in the mammalian master clock — the mPer1 mutant mice [15], which show factors CLOCK and BMAL induces the suprachiasmatic nucleus (SCN) — as an enhanced phase delay response to expression of its own repressors — the well as in peripheral tissues (e.g., heart continuous treatments of light (e.g., PER and CRY proteins [3]. Duffield and and liver) and in serum-stimulated 8 hours and 12 hours) but do not exhibit colleages [8] introduce a new element fibroblasts [11–13]. Conceptually, the a different phase response curve