View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Current Biology, Vol. 13, R433–R435, May 27, 2003, ©2003 Elsevier Science Ltd. All rights reserved. DOI 10.1016/S0960-9822(03)00363-4 Synaptic Transmission: Functional Dispatch Autapses in the Cortex John M. Bekkers Although GABAergic interneurons are extremely diverse [15], some types can be fairly unambiguously distin- guished by the way they fire action potentials during a Autapses — synapses made by a neuron onto itself step depolarization. For example, cortical basket cells — have often been observed anatomically in vivo, are fast-spiking during a step — hence, FS cells — but their purpose has remained uncertain. A recent whereas double bouquet cells fire low-threshold spikes paper describes functional autapses in the cerebral — hence, LTS cells. cortex and gives clues to their physiological role. Armed with this information, Bacci and colleagues [4] went looking for autaptic inhibitory currents in cortical FS cells, which should correspond to the In a complex, evolved biological structure like the brain basket cells identified by Tamás et al. [14] as having it is perhaps not surprising to find that the wiring is not abundant autapses. Sure enough, following a brief as perfect as in an engineered device like a computer. depolarizing stimulus that evoked an action potential, Normally we think of the brain as an assembly of dis- they observed a relatively large (~350 pA, on average) crete neurons connected in a daisy-chain manner via transient current in the same cell. This current had all synapses; but it is also common to find untidy, perhaps the features expected of an autaptic GABA-mediated inadvertent, types of connections that might be called response: it had the right pharmacology; the kinetics ‘short circuits’. One class of these involves the spillover were correct; it fluctuated in amplitude and sometimes of neurotransmitter from the synaptic cleft onto sur- failed, as expected for a synaptic release process; and rounding cells [1]. Another involves specialized the current showed significant paired-pulse depres- synapse-like structures that, surprisingly, form between sion. Furthermore, the currents were common in FS the axon of a neuron and its own soma or dendrites — cells (85% of recordings) but were not seen at all in ‘autapses’, not to be confused with sites of self-excita- LTS neurons (which presumably correspond to the tion or self-inhibition that lack synaptic specializations autapse-lacking double bouquet cells). [2,3]. In accordance with this view of them as aberrant Could a regular synapse masquerade as an autapse structures, autapses have so far seemed like curiosi- in this experiment, perhaps through the disynaptic acti- ties, of unknown practical utility. A new paper [4] invites vation of an intermediary? This seems unlikely, both us to revise this view, by showing that autapses in the because of the short latency of the observed current, neocortex may have a physiological purpose after all. and because it would require that the (inhibitory) Anatomically, autapses are not uncommon in the basket cell somehow excite another interneuron to brain. They have been observed in a variety of brain release GABA back onto the first. Furthermore, Bacci regions, including the striatum, substantia nigra, hip- et al. [4] provided another elegant piece of evidence pocampus, and neocortex [5–11]. The puzzle has been that these were truly autaptic currents. They included that they seem to be functionally invisible. Autaptic in their electrodes the calcium chelator BAPTA, which inhibitory currents have been recorded in stellate and is known to block synaptic transmission at a presy- basket cells in the cerebellum [12], but the currents are naptic intracellular site. They found that internal BAPTA weak and their role unclear. Others have tried, without blocked their putative autaptic responses, indicating success, to record autaptic excitatory potentials in that the postsynaptic cell is presynaptic to itself. neocortical layer 5 pyramidal neurons, where morpho- All of these experiments were done with standard logical autapses are present [10]. These results sug- whole-cell patch clamping, in which the recorded cell gested that the number of autapses per neuron was is filled with the electrode solution. In their case, the simply too small (at least in vivo; they are plentiful in solution contained an unphysiologically high concen- cultures [13]). The suspicion thus arose that autapses tration of chloride in order to exaggerate the size of in vivo may just be a wiring error. GABAergic autaptic currents and make them easier to Then, in 1997, Tamás and colleagues [14] showed see. What do these autapses look like under more anatomically that some types of GABA-releasing physiological conditions? To address this, Bacci et al. inhibitory interneuron in the visual cortex — basket cells [4] turned to gramicidin-perforated whole-cell record- and dendrite-targeting cells — formed relatively large ing, which preserves the normal intracellular chloride numbers of autapses (~10–30). In contrast, another type concentration of the cell and so the normal amount of of interneuron, double bouquet cells, only rarely did so inhibition. Interestingly, under these conditions they [14]. This indicated that electrophysiologists should did not report seeing a hyperpolarizing inhibitory post- look at basket or dendrite-targeting cells for functional synaptic potential (IPSP) following the autaptic stimu- autapses. How might these cell types be identified in lus, implying that the resting potential of their cells is living tissue, where their morphologies are indistinct? close to the IPSP reversal potential. Although autaptic stimulation did not produce an Division of Neuroscience, John Curtin School of Medical obvious change in membrane potential, it still affected Research, Australian National University, Canberra, ACT 0200, the excitability of the cell. Excitability was probed by Australia. applying two brief depolarizing current steps in quick Dispatch R434 Figure 1. Two experiments used by Bacci A Autapses intact Autapses blocked et al. [4] to reveal the feedback inhibition produced by inhibitory autapses. (A) Two brief, depolarizing current steps Iinj (Iinj) are applied to the cell in quick suc- cession. The first step evokes an action potential (Vm), which in turn elicits an autaptic conductance (gaut) in the same cell. The resultant shunting inhibition sup- presses an action potential response to 40 mV the second current step (left panel). When the autaptic conductance is pharma- Vm cologically blocked by gabazine, both 10 ms current steps elicit action potentials (right panel). (B) A prolonged depolarizing current step is applied to the cell, eliciting a train of action potentials. Early in the train, in the absence of gabazine, gaut gaut shunts the cell slightly, making it less excitable and delaying the second action potential (black trace, left panel). After the autapses are blocked by gabazine, the B Early in train Late in train delay to the second action potential is reduced (red trace). Late in the train the autaptic conductance is much reduced Iinj because of accumulated paired-pulse depression. Adding gabazine now has little effect on spike timing (red and black 40 mV traces overlay). 10 ms Vm gaut Current Biology succession, and measuring the likelihood of eliciting excitatory pyramidal neurons. It is interesting that the an action potential on the second step (Figure 1A). only autapses of any consequence in vivo seem to be It was found that this likelihood increased after a found on interneurons. Apart from the obvious state- GABA antagonist was applied to block the autapses, ment that excitatory neurons could be unstable if suggesting that autapses normally provide feedback self-excitatory, this may be because excitatory cells inhibition onto the cell, suppressing the second of two have other simple strategies for feedback inhibition, closely spaced spikes. The mechanism likely involves involving a single inhibitory cell (Figure 2A). On the the well-known phenomenon of shunting inhibition, other hand, without autaptic inhibition, interneurons whereby an increase in membrane conductance can would need to be embedded in a more elaborate short-circuit the membrane and alter excitability circuit to achieve a similar end, at a cost of time without visible alterations in membrane potential. delays (Figure 2B,C). Bacci et al. [4] also showed that this autaptic feed- Self-inhibition by interneurons could also be back inhibition affected repetitive firing of the interneu- accomplished by the potassium channel-mediated ron. When inhibition was intact, the time between afterhyperpolarization (AHP) that typically follows an successive spikes was increased, but only for the first action potential. But apart from the heavily modulated few spikes in a train. Beyond this, the autaptic inhibi- slow AHP — which, interestingly, is not often found in tion underwent paired-pulse depression and had no interneurons [16] — autaptic self-inhibition is far more further effect on spike timing (Figure 1B). plastic than is the typical AHP. Autapses are subject Both of these assays of autaptic inhibition revealed to synaptic depression, quantal fluctuations, receptor effects that were rather subtle, but they provide the desensitization and modulation of transmitter uptake, first evidence that autapses in vivo might have func- any