Pass-Through Code of Synaptic Integration
Authors: Gergely G Szabo, Ivan Soltesz
Journal: Neuron (2015)

How do the components of neuronal circuits collaborate to select combinations of synaptic inputs from multiple pathways? In this issue of Neuron, Milstein et al., 2015Milstein A.D. Bloss E.B. Apostolides P.F. Vaidya S.P. Dilly G.A. Zemelman B.V. Magee J.C. Neuron. 2015; 87 (this issue): 1274-1289Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar uncover mechanisms of synaptic facilitation and dendritic inhibition that cooperate to provide filtering for co-active inputs of distinct origins. How do the components of neuronal circuits collaborate to select combinations of synaptic inputs from multiple pathways? In this issue of Neuron, Milstein et al., 2015Milstein A.D. Bloss E.B. Apostolides P.F. Vaidya S.P. Dilly G.A. Zemelman B.V. Magee J.C. Neuron. 2015; 87 (this issue): 1274-1289Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar uncover mechanisms of synaptic facilitation and dendritic inhibition that cooperate to provide filtering for co-active inputs of distinct origins. Although steeplechase jockeys no longer steer their course directed toward a church steeple, the steeplechase still remains a challenge in which competitors must jump a variety of formidable hurdle and ditch obstacles to conquer the course. In the neuronal version of the steeplechase, multitudes of synaptic inputs arriving at neurons face an even more challenging task in their competition to influence spiking output, because the hurdles themselves are not fixed but can rapidly change depending on a number of factors, including the spatio-temporal clustering of synaptic inputs. What is the nature of these dynamic filters that appear to endow neuronal circuits with the awesome capacity of determining which inputs are to be suppressed or amplified and thus transformed into the spike pattern that represents the circuit's output? In a study published in the present issue of Neuron, Milstein et al., 2015Milstein A.D. Bloss E.B. Apostolides P.F. Vaidya S.P. Dilly G.A. Zemelman B.V. Magee J.C. Neuron. 2015; 87 (this issue): 1274-1289Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar identify novel components of the multi-scale integration machinery that cooperate to enable microcircuits to selectively attenuate or boost signals from multiple input pathways. Cortical circuits in the mammalian CNS exhibit certain basic organizational principles that serve key roles in neuronal computations regardless of the actual nature of the incoming signals. Such near-universal features include the selective innervation of principal cells' particular somato-dendritic domains by incoming excitatory afferents and local inhibitory interneurons, the target-selective short-term plasticity rules that govern the dynamics of presynaptic neurotransmitter release, and the passive and active properties of the postsynaptic dendrites resulting from the highly regulated expression of voltage-gated ion channels along the somato-dendritic axis. Milstein et al., 2015Milstein A.D. Bloss E.B. Apostolides P.F. Vaidya S.P. Dilly G.A. Zemelman B.V. Magee J.C. Neuron. 2015; 87 (this issue): 1274-1289Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar employ the CA1 area of the hippocampus in vitro as a model system to comprehensively examine these multi-scale mechanisms that underlie signal transformation and input feature selectivity by neuronal circuits. The CA1 circuit has the advantage of lacking significant recurrent excitatory connections between its output neurons, the pyramidal cells, and receiving incoming excitation from two well-defined, major input pathways. These include a proximal (i.e., impinging on dendrites closer to the soma) input from the CA3 region of the hippocampus and a more distal input from afferents from layer III of the entorhinal cortex (ECIII). Stimulation of either of these two afferent pathways in brief bursts of three stimuli at within-burst intervals shorter than 300 ms produced excitatory postsynaptic potentials (EPSPs) in the apical trunk dendrites of pyramidal cells that were larger than what could be obtained by simple addition of individually elicited EPSPs. This so-called supralinear summation could result from use-dependent increase in the probability of glutamate release as well as from the postsynaptic boosting of EPSPs by active dendritic conductances, which together comprise the "excitatory synaptic filter." However, the incoming excitation also engages the local GABAergic microcircuit whose various dynamic components together act as the "inhibitory filter" to reduce EPSP summation. These components include short-term plasticity at the excitatory synapses on interneurons, postsynaptic integration in the interneurons themselves, and the inhibitory interactions between the interneurons. Importantly, the excitatory and inhibitory filters showed strong sensitivity to the frequency of the incoming signals, and Milstein et al., 2015Milstein A.D. Bloss E.B. Apostolides P.F. Vaidya S.P. Dilly G.A. Zemelman B.V. Magee J.C. Neuron. 2015; 87 (this issue): 1274-1289Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar performed recordings from three major interneuronal types innervating distinct parts of the pyramidal cells and employed pharmacological blockade of GABAergic inhibition to demonstrate that the CA1 microcircuit appears to act as a high-pass filter, with excitatory inputs closely paced in time having the greatest chance of overcoming the dynamic filters. Because the preferential pass-through of high-frequency inputs was observed for both ECIII and CA3 afferents, Milstein et al., 2015Milstein A.D. Bloss E.B. Apostolides P.F. Vaidya S.P. Dilly G.A. Zemelman B.V. Magee J.C. Neuron. 2015; 87 (this issue): 1274-1289Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar next examined the properties of the filters when both inputs were activated, using a stimulation protocol that mimicked the in vivo patterns of afferent activity during exploration. One of the characteristic features of hippocampal networks is the presence of theta oscillation during locomotion (as well as during REM sleep) that emerges as an ongoing slow, 5 Hz to 10 Hz rhythm in the local field potential that is thought to provide distinct temporal windows for the firing of different neuronal groups (Klausberger and Somogyi, 2008Klausberger T. Somogyi P. Science. 2008; 321: 53-57Crossref PubMed Scopus (1428) Google Scholar, Varga et al., 2014Varga C. Oijala M. Lish J. Szabo G.G. Bezaire M. Marchionni I. Golshani P. Soltesz I. eLife. 2014; 3: 3Crossref Scopus (71) Google Scholar). The ECIII and CA3 inputs tend to arrive at different phases of the theta cycle in vivo (Mizuseki et al., 2009Mizuseki K. Sirota A. Pastalkova E. Buzsáki G. Neuron. 2009; 64: 267-280Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar, Schomburg et al., 2014Schomburg E.W. Fernández-Ruiz A. Mizuseki K. Berényi A. Anastassiou C.A. Koch C. Buzsáki G. Neuron. 2014; 84: 470-485Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar). Accordingly, the ECIII and CA3 inputs were activated in repeated theta-frequency burst patterns, with the ECIII preceding the CA3 inputs by the experimentally observed temporal offset. Stimulation of the afferents with this naturalistic paradigm caused supralinear summation within each theta cycle that often resulted in action potential firing. The ECIII and CA3 inputs by themselves were also able to generate spiking; however, the supralinear summation was more pronounced when both inputs were activated, producing a higher firing rate in the pyramidal cells. A prior study by the Magee group showed that the properly timed stimulation of ECIII and CA3 inputs could initiate robust, so-called dendritic plateau potentials in the distal dendrites of CA1 pyramidal cells (Takahashi and Magee, 2009Takahashi H. Magee J.C. Neuron. 2009; 62: 102-111Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar). In the present work, these regenerative dendritic events driving complex spike bursts are also observed when the theta burst stimulation is applied to both inputs, but only in the complete absence of inhibition. This finding suggests that a specialized inhibitory filter that may exist to effectively gate the dendritic summation of the co-activated ECIII and CA3 inputs. What might be the nature of the inhibitory filter that could regulate dual pathway integration in the CA1? If there were a specialized inhibitory component in the circuit that controlled the dendrites of pyramidal cells and responded to ECIII and CA3 inputs the same way as pyramidal cells do, then such a hypothetical circuit component would be in a perfect strategic position to control the dendritic events elicited by coincident dual pathway activity right after they are generated. The present study proposes a subtype of neuropeptide-Y (NPY)-expressing cell as an attractive candidate for the latter job, most importantly because these GABAergic interneurons possess dendrites that penetrate into layers of CA1 where the ECIII and CA3 afferents terminate, making it possible for the two sets of inputs to simultaneously activate the NPY cells. Indeed, when either ECIII or CA3 inputs were stimulated, NPY cells responded with prominently facilitating excitation that drove them to spike, and stimulation of both pathways in close temporal succession using the above-described theta burst paradigm increased their firing rate even more, rendering them ideally suited for coincidence detection. In order to better delineate the capacity of the proposed NPY cell-based inhibitory filter, the efficacy of three distinct interneuron types were compared using selective optogenetic excitation. Of the interneuron types examined (parvalbumin, somatostatin, and NPY), NPY cells produced the strongest reduction of dendritic spikes elicited by a patch-clamp pipette placed directly in the main apical dendritic trunk, indicating that NPY cells were indeed able to act as powerful guardians of dual pathway integration. The results of this study (Milstein et al., 2015Milstein A.D. Bloss E.B. Apostolides P.F. Vaidya S.P. Dilly G.A. Zemelman B.V. Magee J.C. Neuron. 2015; 87 (this issue): 1274-1289Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar) highlight the nature of the series of spatiotemporal filters that underlie nonlinear signal transformation and the selection of specific input patterns for amplification and propagation to circuits downstream from the CA1. High-frequency, dual pathway signals arriving in rhythmic bursts are integrated in a supralinear manner that may result in pyramidal cell firing. However, a specialized form of feedforward inhibitory filtering from NPY cells effectively regulates dendritic complex spiking and thus the ultimate mode of output. But would it really matter at a functional level if coincident bursts at both ECIII and CA3 input pathways actually succeed in the steeplechase and overcome the series of filters to evoke dendritic complex spikes? For example, could such spikes in some way relate to the firing of CA1 pyramidal cells in their place fields, where the discharge pattern carries information about the position of the animal in physical space? Another recent study from the Magee group (Bittner et al., 2015Bittner K.C. Grienberger C. Vaidya S.P. Milstein A.D. Macklin J.J. Suh J. Tonegawa S. Magee J.C. Nat. Neurosci. 2015; 18: 1133-1142Crossref PubMed Scopus (270) Google Scholar) has already shed light on these intriguing questions by demonstrating that the nonlinear integration of ECIII and CA3 inputs, in awake behaving animals, results in the appearance of dendritic plateau potentials that enhance the incidence of complex burst firing and drive the formation of new place fields. Because the in vitro results of the current study (Milstein et al., 2015Milstein A.D. Bloss E.B. Apostolides P.F. Vaidya S.P. Dilly G.A. Zemelman B.V. Magee J.C. Neuron. 2015; 87 (this issue): 1274-1289Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar) indicate that such regenerative dendritic events are exquisitely sensitive to the presence of inhibition, it is possible that mechanisms exist in vivo that, under relatively rare and specific circumstances, can effectively veto the inhibitory effect of NPY cells to permit the occurrence of plateau potentials and thus place field generation. The nature of such hypothetical mechanisms is not yet known but may include interneuron-specific local or long distance projecting interneurons, subcortical modulatory inputs or some other means. The study by Milstein et al., 2015Milstein A.D. Bloss E.B. Apostolides P.F. Vaidya S.P. Dilly G.A. Zemelman B.V. Magee J.C. Neuron. 2015; 87 (this issue): 1274-1289Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar poses interesting questions about the inhibitory gating of dual pathway integration that future experiments will have to address. For example, it will be important to better understand the properties of the NPY cell subtypes that are responsible for the reported effects and determine how they fire in vivo in behaving animals, particularly during exploration, when new place fields may be generated. These future studies should also determine whether silencing or activation of NPY cells influences spatial memory functions, because if these cells indeed play a key role in controlling dendritic plateau potential-driven complex spiking, manipulations of their activity in vivo should have significant impact on spatial learning. Such experiments may also shed light on pathological mechanisms where a malfunctioning inhibitory filter governed by NPY cells could potentially cause runaway excitation and lead to epileptiform activity. It should also be noted that subtypes of NPY cells are not the only GABAergic interneurons that have dendrites in the layers where ECIII and CA3 afferents terminate within CA1. For example, dendritically projecting cholecystokinin (CCK)-expressing interneurons also can extend dendrites into both of these layers, a feature that is shared even by some perisomatically projecting CCK cells and major classes of fast-spiking, parvalbumin-expressing interneurons (Klausberger and Somogyi, 2008Klausberger T. Somogyi P. Science. 2008; 321: 53-57Crossref PubMed Scopus (1428) Google Scholar, Varga et al., 2014Varga C. Oijala M. Lish J. Szabo G.G. Bezaire M. Marchionni I. Golshani P. Soltesz I. eLife. 2014; 3: 3Crossref Scopus (71) Google Scholar). Indeed, CCK interneurons are recruited by precisely paired ECIII and CA3 inputs and thus can influence back-propagating action potentials on pyramidal cell dendrites that may play a role in generating dendritic plateau potentials (Basu et al., 2013Basu J. Srinivas K.V. Cheung S.K. Taniguchi H. Huang Z.J. Siegelbaum S.A. Neuron. 2013; 79: 1208-1221Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, Bittner et al., 2015Bittner K.C. Grienberger C. Vaidya S.P. Milstein A.D. Macklin J.J. Suh J. Tonegawa S. Magee J.C. Nat. Neurosci. 2015; 18: 1133-1142Crossref PubMed Scopus (270) Google Scholar, Larkum et al., 1999Larkum M.E. Zhu J.J. Sakmann B. Nature. 1999; 398: 338-341Crossref PubMed Scopus (777) Google Scholar). In addition, rules of integration involving other major excitatory inputs to the CA1, such as the thalamic afferents, will also have to be deciphered. Finally, in light of the highly selective GABAergic innervation of the heterogenous subpopulations of CA1 pyramidal cells (Mizuseki et al., 2011Mizuseki K. Diba K. Pastalkova E. Buzsáki G. Nat. Neurosci. 2011; 14: 1174-1181Crossref PubMed Scopus (235) Google Scholar, Lee et al., 2014Lee S.H. Marchionni I. Bezaire M. Varga C. Danielson N. Lovett-Barron M. Losonczy A. Soltesz I. Neuron. 2014; 82: 1129-1144Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar), it will be important to determine whether differentially projecting pyramidal cells located in distinct parts of the CA1 principal cell layer in fact possess different sets of inhibitory and excitatory filters to regulate dual pathway excitatory inputs. Hang on to your fancy hats and fear not, dark horses abound for the jockeys of the neuronal steeplechase. Inhibitory Gating of Input Comparison in the CA1 MicrocircuitMilstein et al.NeuronSeptember 23, 2015In BriefCA3 and ECIII inputs to CA1 target distinct dendritic domains of pyramidal cells and recruit specific classes of interneurons. Milstein et al. quantify contributions by short-term plasticity, dendritic amplification, and compartmentalized inhibition to synaptic filtering dynamics during dual pathway integration. Full-Text PDF Open Archive