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ScienceWeek
NEUROBIOLOGY: SYNAPTOGENESIS, EXCITATION, AND INHIBITION
The following points are made by Hollis Cline (Current Biology 2005 15:R203):
1) Brain function is based on a balance of excitation and inhibition. This is clear from studies of diseases such as epilepsy, where decreased inhibitory inputs leads to massive brain oscillatory activity [1], or Parkinson's disease, in which an imbalance of excitation and inhibition within striatal-thalamo-cortical connections leads to motor and cognitive impairment [2]. An imbalance of excitation and inhibition may underlie several neurological diseases, including autism [3], Tourette's syndrome [4] and schizophrenia [5]. Genetic abnormalities, including point mutations and chromosomal rearrangements, in loci corresponding to the genes for the synaptic proteins neuroligin and PSD95, are apparently associated with autism.
2) In healthy brains, a balance of excitation and inhibition is essential for nearly all functions, including representation of sensory information, cognitive processes such as decision making, sleep and motor control. At the cellular level, the number and distribution of excitatory and inhibitory inputs onto single neurons has significant impact on the integration of synaptic inputs and the output from neurons. This in turn affects circuit function and plasticity, for instance by affecting long-term potentiation or the stereotypic output from central pattern generators. During development, the balance between excitation and inhibition governs the establishment of sensory system projections, including the onset of the critical period for visual system plasticity. Despite the clear importance of balanced excitation and inhibition in brain function, the developmental control of this equilibrium is unknown. Recent studies of the molecular basis of excitatory synapse formation have provided new insights into the mechanisms governing the balance of excitation and inhibition in the CNS.
3) Synapse assembly requires both anterograde and retrograde trans-synaptic signaling, as well as signaling within each presynaptic and postsynaptic component. But the molecular constituents of the trans-synaptic signaling complex have not yet been defined. Signaling between beta-neurexin and neuroligin may orchestrate coordinated presynaptic and postsynaptic development. Neuroligins are a family of postsynaptic transmembrane proteins, which have been shown to induce differentiation of presynaptic structures when expressed in non-neuronal cells. One possibility is that this induction could occur through interaction of neuroligin with the presynaptic transmembrane protein beta-neurexin, but a requirement for this interaction in synaptogenesis has been difficult to demonstrate in vivo because the complexity of the genes involved has taxed traditional knock-out strategies.
4) Recent work provides strong evidence that beta-neurexin-neuroligin signaling indeed promotes synapse formation. The basic findings are that overexpression of neuroligins or beta-neurexin induces presynaptic or postsynaptic differentiation, respectively, of both excitatory and inhibitory synaptic components in hippocampal neurons, while downregulating the level of neuroligin expression by RNA interference (RNAi) inhibited the differentiation and maturation of excitatory and inhibitory synaptic contacts. Overexpression of the postsynaptic density protein PSD95, which is known to increase excitatory synapse formation, recruits neuroligin to clusters of excitatory synaptic proteins, indicating that the trans-synaptic signaling that occurs during synapse formation and the establishment of a matrix of postsynaptic density proteins are mechanistically linked. Electrophysiological recordings further suggest that neuroligins and PSD95 are important for establishment of excitatory versus inhibitory synapses.
5) In summary: Recent studies have implicated a number of membrane-associated proteins, including the signaling pair neuroligin and beta-neurexin, in synapse formation, suggesting that they govern the ratio of inhibitory and excitatory synapses on CNS neurons. These findings, together with data indicating that the genes encoding neuroligin and PSD95 are altered in autism patients, suggest that a molecular understanding of complex neurological diseases is within reach.
References (abridged):
1. Brenner, R.P. (2004). EEG in convulsive and nonconvulsive status epilepticus. J. Clin. Neurophysiol. 21, 319-331
2. Llinas, R.R., Ribary, U., Jeanmonod, D., Kronberg, E., and Mitra, P.P. (1999). Thalamocortical dysrhythmia: A neurological and neuropsychiatric syndrome characterized by magnetoencephalography. Proc. Natl. Acad. Sci. USA 96, 15222-15227
3. Rubenstein, J.L. and Merzenich, M.M. (2003). Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2, 255-267
4. Singer, H.S. and Minzer, K. (2003). Neurobiology of Tourette's syndrome: concepts of neuroanatomic localization and neurochemical abnormalities. Brain Dev. 25, S70-S84
5. Wassef, A., Baker, J., and Kochan, L.D. (2003). GABA and schizophrenia: a review of basic science and clinical studies. J. Clin. Psychopharmacol. 23, 601-640
Current Biology http://www.current-biology.com
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NEUROSCIENCE: ON SYNAPSE PHYSIOLOGY
The following points are made by Martin Wilson (Current Biology 2004 14:R666):
1) The job description for most synapses in the brain includes a great deal of waiting. Every now and then an action potential invades the presynaptic terminal, opens Ca2+ channels and then, with some finite probability, the influx of Ca2+ ions triggers the exocytosis of a vesicle of transmitter. But before and after this millisecond of excitement there are generally long periods when not very much happens. This light workload for synapses is possible for neurons that use the action potential code, but not all neurons use this code. Some primary receptor cells, such as auditory hair cells, photoreceptors, and electroreceptors, as well as some of the interneurons in the retina, signal with graded potentials operating over a range of a few tens of millivolts.
2) For neurons of this latter kind, transmitter has to be released continuously and at a sufficiently high rate that small changes in voltage can be adequately resolved as changes in release rate. Ultimately, our ability to discriminate light from dark, and quiet from loud, depends upon these synapses and unraveling their mechanism has stimulated some of the cleverest experiments in all of recent cellular neuroscience, and yet conclusive answers to many of the most basic questions remain tantalizingly just out of reach. But recent reports [1-3] have brought us a little closer to answers for two of the most important questions: How does Ca2+ control transmitter release? And what is the function of synaptic ribbons?
3) Since Ca2+ is the messenger that triggers transmitter release, the details of the relationship between Ca2+ concentration and transmitter release are crucially important, not only for understanding the working of synapses, but also as a clue to the molecules involved in exocytosis. Are graded synapses and action potential synapses similar with respect to Ca2+? It is beginning to look as though there may be no general answers, only particular answers.
4) It was thought that action potential synapses require heroic concentrations of Ca2+, in excess of 100 micromolar [4], in other words about one thousand-fold above resting concentration. However, examination of a large action potential synapse in the vertebrate brainstem called the Calyx of Held showed that the Ca2+ threshold for transmitter release lies around a few micromolar [5]. At the Calyx of Held, the rate of exocytosis depends on Ca2+ concentration raised to the fourth or fifth power, implying that five Ca2+ ions cooperate in the exocytosis of a single vesicle. This cooperativity, first described at the neuromuscular junction, is thought to obtain at other action potential synapses where it speeds the turning on and turning off of transmission and also renders the synapse exquisitely sensitive to small differences in Ca2+ concentration.
References (abridged):
1 Thoreson, W.B.X Rabl, K.X Townes-Anderson, E. and Heidelberger, R. (2004). A highly Ca2+-sensitive pool of vesicles contributes to linearity at the rod photoreceptor ribbon synapse. Neuron 42, 595-605
2 Rea, R.X Li, J.X Dharia, A.X Levitan, E.S.X Sterling, P. and Kramer, R.H. (2004). Streamlined synaptic vesicle cycle in cone photoreceptor terminals. Neuron 41, 755-766
3 Holt, M.X Cooke, A.X Neef, A. and Lagnado, L. (2004). High mobility of vesicles supports continuous exocytosis at a ribbon synapse. Curr. Biol. 14, 173-183
4 Llinas, R.X Sugimori, M. and Silver, R.B. (1992). Microdomains of high calcium concentration in a presynaptic terminal. Science 256, 677-679
5 Bollmann, J.H.X Sakmann, B. and Borst, J.G. (2000). Calcium sensitivity of glutamate release in a calyx-type terminal. Science 289, 953-957
Current Biology http://www.current-biology.com
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NEUROBIOLOGY: SYNAPSES, NEUREXINS, AND CALCIUM CHANNELS
Notes by ScienceWeek:
Neurexins are a family of neuronal cell surface proteins with apparent roles in cell adhesion and intercellular signaling. Three distinct genes encoding neurexins have been identified in vertebrates. The neurexins have been grouped with several other proteins into a "superfamily". In general, in this context, a "superfamily" is any group of genes and their cognate proteins that can be related by sequence homology.
The following points are made by J.T. Littleton and Morgan Sheng (Nature 2003 423:931):
1) The computational power of the brain depends on the precise connections, or synapses, that link together the many billions of nerve cells. Specialized to allow rapid (millisecond) neuronal communication, synapses work broadly as follows. In response to an electrical impulse, the terminal of a "presynaptic" neuron releases chemical neurotransmitters, which diffuse across the synaptic cleft to activate specific receptors on the postsynaptic neuron. These receptors cause an electrical discharge in the postsynaptic cell, thereby propagating the electrical signal.
2) More specifically, since the classic work of Bernard Katz(2), it has been known that electrical impulses propagating down a neuron cause an influx of calcium ions through voltage-gated calcium channels in the presynaptic nerve terminal; this in turn triggers neurotransmitter release. The rapidity with which calcium influx leads to neurotransmitter release (within 200 microseconds) means that the voltage-gated calcium channels must be very close to -- perhaps even physically associated with --the molecular machinery that releases the neurotransmitter from the cell(3,4). Furthermore, the presynaptic and postsynaptic elements of the synapse must be aligned, such that neurotransmitter release occurs at sites precisely opposite clusters of neurotransmitter receptors in the postsynaptic membrane. An attractive idea is that this alignment is achieved by adhesion molecules -- specific cell-surface proteins located on both sides of the synapse that grip each other across the synaptic cleft and hold the presynaptic and postsynaptic apparatuses in register.
3) One family of cell-surface proteins implicated in synapse formation and adhesion is the neurexins. Originally identified by their binding to alpha-latrotoxin(5) (a spider toxin that triggers neurotransmitter release), the neurexins are presynaptic transmembrane proteins that have a large extracellular region and a short intracellular tail. A striking feature of neurexins is their molecular diversity: they are encoded by three genes, each of which has two regulatory regions; this means that long (alpha) and short (beta) neurexin proteins can be generated from each gene. In addition, the messenger RNAs encoded by each gene can be processed in different ways (by "alternative splicing"), resulting in thousands of distinct protein forms.
4) Because of their great diversity and their presence on the surface of presynaptic terminals, neurexins became attractive candidates for determining the specificity of synaptic connections. Consistent with this idea, specific neurexin proteins bind through their extracellular domain to neuroligins, a family of transmembrane receptors found in the postsynaptic membrane, and to dystroglycan, a cell-surface protein of unknown function in the brain. The interaction of neuroligin and neurexin in cultured neurons induces morphological events resembling synapse formation, implying that neurexins function in the specification and initiation of synapse formation.
5) Recent genetic analysis has shifted our view of neurexins: it seems that they are not needed for synapses to form or to achieve specificity of neuronal connections. Instead, Missler et al(1) propose that neurexins are essential for the molecular and functional integration of calcium channels with the basic presynaptic release machinery. Moreover, by binding "trans-synaptically" to specific postsynaptic proteins, neurexins could offer a simple means of restricting the activity (and/or localization) of presynaptic calcium channels to specific sites.
References (abridged):
1. Missler, M. et al. Nature 423, 939-948 (2003)
2. Katz, B. & Miledi, R. Proc. R. Soc. Lond. B Biol. Sci. 161, 496-503 (1965)
3. Smith, S. J. & Augustine, G. J. Trends Neurosci. 11, 458-464 (1988)
4. Atlas, D. J. Neurochem. 77, 972-985 (2001)
5. Ushkaryov, Y. A., Petrenko, A. G., Geppert, M. & Suedhof, T. C. Science 257, 50-56 (1992)
Nature http://www.nature.com/nature
ScienceWeek http://scienceweek.com
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