Current Biology, Vol. 12, 000–000, May, 2002, 2002 Elsevier Science Ltd. All rights reserved. PII S0960-9822(02)000-X Cerebellar Cortex: Computation by Dispatch Extrasynaptic Inhibition? Erik De Schutter GABA concentration in glomeruli can activate some GABA receptors. Several lines of evidence support the view that In the cerebellar cortex, inhibitory inputs to granule spillover transmission also makes a contribution. First, cells exhibit prominent tonic and spillover compo- two different kinds of synaptic current can be nents resulting from the activation of extrasynaptic recorded in a granule cell following Golgi cell stimula- receptors. A recent study shows how extrasynaptic tion: fast responses with time courses similar to spon- inhibition affects information flow through cerebel- taneous events, and much slower responses with a lar cortex. slow decay . Second, granule cells in the cerebel- lum and cochlear nucleus are the only cells that express the α subunit of the GABA receptor . The cerebellar cortex contains more granule cells than Receptors containing the α δ subunit combination there are neurons in the rest of the brain, but compar- have a 50-fold higher affinity for GABA than other atively little is known about their function compared to GABA receptors, and they do not desensitize upon the more striking Purkinje cells. Cerebellar granule prolonged presence of agonist . The δ subunit is cells are, however, a popular preparation for pharma- found exclusively in extrasynaptic locations on the cological studies of receptors and channels. A long dendrites and somata of granule cells . The tonic series of studies of granule cell receptors for the and evoked slow currents recorded from granule cells inhibitory neurotransmitter γ-amino butyric acid both have the pharmacological profile of a receptor (GABA) has now led to some fundamental insights into containing α and δ subunits, being furosemide- how a characteristic anatomical specialization of the sensitive but diazepam- and neurosteroid-insensitive cerebellar cortex, the glomerulus, may work . [1, 4]. Taken together, these observations strongly Glomeruli are formed around the large axonal termi- suggest that the slow evoked currents reflect the nals of glutamatergic mossy fiber afferents (Figure 1). activation of extrasynaptic α β
δ receptors by GABA Each terminal is contacted by dendrites from 50–60 molecules that have ‘spilled over’ from activated distinct granule cells. The glomeruli also contain synapses on other granule cells in the same glomeru- GABAergic synapses that inhibitory Golgi cells make lus. The diffusion boundaries caused by the glomeru- with the granule cells, and glutamatergic contacts lar sheath may further promote extrasynaptic between the mossy fibers and Golgi cells. The struc- interaction between granule cells. ture has a radius of about 2.5 µm and is enwrapped by It was always assumed that the extrasynaptic glial sheathing. Granule cells have one to eight den- activation of GABA receptors might have an impor- drites, each participating in a different glomerulus. tant role in cerebellar processing, but until recently The first indication that GABAergic inhibition of there has been little experimental evidence for such a granule cells has unusual properties came from the notion. In mature animals, where most of the sponta- discovery that it has a strong tonic component [2,3]. neous GABA current is tonic, blocking all GABA This tonic GABA current is much larger than that receptors with bicuculline leads to increased evoked by spontaneous events and can be completely responses of granule cells to current injection . blocked by the GABA receptor antagonist bicu- Much progress has now been made by using culline; its fraction of the total GABA current increases furosemide to specifically block GABA receptors that from 5% in young to 99% in mature rats . An attrac- have an α subunit in cerebellar slices from adult tive hypothesis is that this phenomenon is caused by animals . Using this approach, it is estimated that spillover of GABA molecules between neighboring 97% of the charge evoked during Golgi cell stimula- Golgi-to-granule cell synapses of the same glomeru- tion flows through extrasynaptic GABA receptors! lus. The initiating event would still be action potential- This fraction includes the tonic current, which evoked GABA release, but because the release accounts for 75% of the charge transfer. These happens at relatively distant synapses, diffusion and measurements were, however, made at 29° and tonic the summation of multiple events will result in delays inhibition may make a much smaller contribution at which will act to filter out the synaptic transients. If the body temperature . Specifically blocking extrasy- tonic current is indeed caused by GABA spillover, then naptic GABA receptors with furosemide causes a one would expected it to be blocked by tetrodotoxin leftward shift of the firing curve of granule cells, as or low external calcium. These manipulations partially expected for the removal of a shunting inhibition , block the tonic current in young animals and not at all but it has no effect on the excitability of other neurons in adult ones [1–3], so it is assumed that the ambient in the cerebellar cortex. But how will the altered excitability of granule cells Theoretical Neurobiology, Born-Bunge Foundation, University that results from extrasynaptic inhibition affect infor- of Antwerp, Universiteitsplein 1, B2610 Antwerp, Belgium. mation transfer in the cerebellar cortex? This is not E-mail: email@example.com easy to predict as additional properties of the circuitry Dispatch R2 need to be taken into account. An increase in granule Golgi cell afterhyperpolarization , unless one can cell activity resulting from a blockade of extrasynaptic assume mechanisms which prolong the effect of each inhibition would also enhance Golgi cell activity Golgi cell spike. While the synaptic GABA channels through excitatory contacts made by parallel fibers already have relatively slow kinetics, the much slower , which may lead to increased synaptic GABA spillover mechanism seems well suited to having a release. Besides its inhibitory effect on granule cells, function in gain control. As a result of spillover, this may also activate GABA receptors on mossy increased Golgi cell activity — through either direct fibers. It has been shown that such receptors are mossy fiber activation or indirect parallel fiber activa- activated by GABA spillover and reduce evoked tion — will reduce excitability of all granule cells par- mossy fiber responses in granule cells at low stimula- ticipating in a glomerulus. This would provide for tion frequencies . Multiple effects on Purkinje cells rather a slow gain control mechanism, which may not are possible, as they are both directly activated by prevent fast swings in granule cell activity . increased parallel fiber activity and inhibited by But how does the stronger tetrodotoxin-resistant stellate/basket cells which also receive parallel fiber tonic inhibition fit into this picture? It could provide a constant baseline, raising the threshold for spike In their recent study, Hamann et al.  measured initiation in granule cells. But if this is desired, it seems the effect of blocking extrasynaptic GABA receptors more straightforward to reduce the intrinsic excitabil- with furosemide on the input and output elements of ity of granule cells, as observed in transgenic mice the pathway. They found that the resulting enhanced that lack the GABA receptor α and δ subunits and excitability of the granule cells increases the number so have no tonic current . A more attractive idea is of spikes they fire in response to mossy fiber stimula- that tonic inhibition itself is regulated somehow. This tion by about 100%. Purkinje cells also increase their could occur at the receptor side, for example by phos- firing frequency in response to mossy fiber stimulation phorylation depending on β subunit expression , or by about 100%. These increases reflect an increase in by changing the baseline GABA concentration in the the size of evoked excitatory postsynaptic potentials glomerulus. Reduced tonic inhibition may explain the (EPSPs), corresponding to a larger number of co-acti- evidence for spike-mediated inhibition in vivo [13,17], vated parallel fiber synapses. In conclusion, blocking which is difficult to reconcile with the in vitro observa- extrasynaptic inhibition increases the flow of neural tion that only 3% of the GABA current is spike medi- activity through cerebellar cortex — and conversely, ated . If tonic inhibition is regulated, it could have the tonic inhibition normally present reduces this flow. additional effects beyond controlling information flow What may be the functional impact of the reduction through the cerebellum. Long-term potentiation (LTP) in activity transmission caused by extrasynaptic inhi- of mossy fiber-to-granule cell synapses can only be bition? Hamann et al.  refer to David Marr’s  reliably evoked in vitro when inhibition is blocked . seminal work on cerebellar motor learning to suggest Any mechanism that reduces tonic inhibition will that decreasing the number of granule cells activated enhance LTP of this synapse. If it turns out that by mossy fiber input increases the storage capacity of extrasynaptic inhibition can be regulated separately in the cerebellum. This is actually a simplification of what each individual glomerulus, there could be very inter- Marr really wrote — that Golgi cell inhibition should esting implications for the possible computational keep “the numbers of active parallel fibres . reason- functions of the glomerulus. ably small over quite large variation in the number of active mossy fibres” . In other words, there should References Hamann, M., Rossi, D.J. and Attwell, D. (2002). Tonic and spillover be a dynamic component to the inhibition of granule inhibition of granule cells control information flow through cerebel- cell activity, stronger when many mossy fibers are lar cortex. Neuron 33, 625–633. active and weaker when few are firing. This was called Wall, M.J. and Usowicz, M.M. (1997). Development of action poten- ‘automatic gain control’ by Albus . The anatomy tial-dependent and independent spontaneous GABA receptor- mediated currents in granule cells of postnatal rat cerebellum. 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GABA(A) receptors: immunocytochemical distribution of in response to natural stimulation , followed by a 13 subunits in the adult rat brain. Neuroscience 101, 815–850. long pause due to afterhyperpolarization . More- Saxena, N.C. and Macdonald, R.L. (1996). Properties of putative cerebellar gamma-aminobutyric acid A receptor isoforms. Mol. over, spike-evoked inhibition by Golgi cells in vivo is Pharmacol. 49, 567–579. strong enough to cause the theoretically predicted Nusser, Z., Sieghart, W. and Somogyi, P. (1998). Segregation of dif-  synchronization of Golgi cell activity along the ferent GABA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells. J. Neurosci. 18, 1693–1703. parallel fiber beam [16,17]. The Golgi cell firing pattern Mitchell, S.J. and Silver, R.A. (2000). 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D’Angelo, E., Rossi, P., Armano, S. and Taglietti, V. (1999). Evidence for NMDA and mGlu receptor-dependent long-term potentiation of mossy fiber-granule cell transmission in rat cerebellum. J. Neuro- physiol. 81, 277–287. Figure 1. Synaptic elements in a glomerulus of the cerebellar cortex. Excitatory synapses are represented by triangles and inhibitory ones by circles.
Management of Type 2 Diabetes Sorting Through the Confusion and Current Clinical Recommendations for Management An Overview for Pharmacists and Pharmacy Technicians Mary Jo Carden, RPh, JD Principal, Carden Associates Marsha K. Millonig, MBA, RPh President/CEO Catalyst Enterprises, LLC E.L.F. Publications, Inc. is accredited by the Accreditation Council for Ph
Writ Petition No. 4361 of 2009 In the matter of: An application under Article 102 of the Constitution of the People’s Republic of Bangladesh. In the matter of: Sheikh Md. Romij Uddin (Tara Miah) and another Mr. Majedul Islam Patwary with Mr. Syed Hasan Zahir, Advocates Heard on 28.9.2010 and Judgment on 04.10.2010 Present: Ms. Justice Nazmun Ara Sultana And Mr. Justi