@article{10816, abstract = {Pattern separation is a fundamental brain computation that converts small differences in input patterns into large differences in output patterns. Several synaptic mechanisms of pattern separation have been proposed, including code expansion, inhibition and plasticity; however, which of these mechanisms play a role in the entorhinal cortex (EC)–dentate gyrus (DG)–CA3 circuit, a classical pattern separation circuit, remains unclear. Here we show that a biologically realistic, full-scale EC–DG–CA3 circuit model, including granule cells (GCs) and parvalbumin-positive inhibitory interneurons (PV+-INs) in the DG, is an efficient pattern separator. Both external gamma-modulated inhibition and internal lateral inhibition mediated by PV+-INs substantially contributed to pattern separation. Both local connectivity and fast signaling at GC–PV+-IN synapses were important for maximum effectiveness. Similarly, mossy fiber synapses with conditional detonator properties contributed to pattern separation. By contrast, perforant path synapses with Hebbian synaptic plasticity and direct EC–CA3 connection shifted the network towards pattern completion. Our results demonstrate that the specific properties of cells and synapses optimize higher-order computations in biological networks and might be useful to improve the deep learning capabilities of technical networks.}, author = {Guzmán, José and Schlögl, Alois and Espinoza Martinez, Claudia and Zhang, Xiaomin and Suter, Benjamin and Jonas, Peter M}, issn = {2662-8457}, journal = {Nature Computational Science}, keywords = {general medicine}, number = {12}, pages = {830--842}, publisher = {Springer Nature}, title = {{How connectivity rules and synaptic properties shape the efficacy of pattern separation in the entorhinal cortex–dentate gyrus–CA3 network}}, doi = {10.1038/s43588-021-00157-1}, volume = {1}, year = {2021}, } @misc{10110, abstract = {Pattern separation is a fundamental brain computation that converts small differences in input patterns into large differences in output patterns. Several synaptic mechanisms of pattern separation have been proposed, including code expansion, inhibition and plasticity; however, which of these mechanisms play a role in the entorhinal cortex (EC)–dentate gyrus (DG)–CA3 circuit, a classical pattern separation circuit, remains unclear. Here we show that a biologically realistic, full-scale EC–DG–CA3 circuit model, including granule cells (GCs) and parvalbumin-positive inhibitory interneurons (PV+-INs) in the DG, is an efficient pattern separator. Both external gamma-modulated inhibition and internal lateral inhibition mediated by PV+-INs substantially contributed to pattern separation. Both local connectivity and fast signaling at GC–PV+-IN synapses were important for maximum effectiveness. Similarly, mossy fiber synapses with conditional detonator properties contributed to pattern separation. By contrast, perforant path synapses with Hebbian synaptic plasticity and direct EC–CA3 connection shifted the network towards pattern completion. Our results demonstrate that the specific properties of cells and synapses optimize higher-order computations in biological networks and might be useful to improve the deep learning capabilities of technical networks.}, author = {Guzmán, José and Schlögl, Alois and Espinoza Martinez, Claudia and Zhang, Xiaomin and Suter, Benjamin and Jonas, Peter M}, publisher = {IST Austria}, title = {{How connectivity rules and synaptic properties shape the efficacy of pattern separation in the entorhinal cortex–dentate gyrus–CA3 network}}, doi = {10.15479/AT:ISTA:10110}, year = {2021}, } @article{21, abstract = {Parvalbumin-positive (PV+) GABAergic interneurons in hippocampal microcircuits are thought to play a key role in several higher network functions, such as feedforward and feedback inhibition, network oscillations, and pattern separation. Fast lateral inhibition mediated by GABAergic interneurons may implement a winner-takes-all mechanism in the hippocampal input layer. However, it is not clear whether the functional connectivity rules of granule cells (GCs) and interneurons in the dentate gyrus are consistent with such a mechanism. Using simultaneous patch-clamp recordings from up to seven GCs and up to four PV+ interneurons in the dentate gyrus, we find that connectivity is structured in space, synapse-specific, and enriched in specific disynaptic motifs. In contrast to the neocortex, lateral inhibition in the dentate gyrus (in which a GC inhibits neighboring GCs via a PV+ interneuron) is ~ 10-times more abundant than recurrent inhibition (in which a GC inhibits itself). Thus, unique connectivity rules may enable the dentate gyrus to perform specific higher-order computations}, author = {Espinoza Martinez, Claudia and Guzmán, José and Zhang, Xiaomin and Jonas, Peter M}, journal = {Nature Communications}, number = {1}, publisher = {Nature Publishing Group}, title = {{Parvalbumin+ interneurons obey unique connectivity rules and establish a powerful lateral-inhibition microcircuit in dentate gyrus}}, doi = {10.1038/s41467-018-06899-3}, volume = {9}, year = {2018}, } @article{1432, abstract = {CA3–CA3 recurrent excitatory synapses are thought to play a key role in memory storage and pattern completion. Whether the plasticity properties of these synapses are consistent with their proposed network functions remains unclear. Here, we examine the properties of spike timing-dependent plasticity (STDP) at CA3–CA3 synapses. Low-frequency pairing of excitatory postsynaptic potentials (EPSPs) and action potentials (APs) induces long-term potentiation (LTP), independent of temporal order. The STDP curve is symmetric and broad (half-width ~150 ms). Consistent with these STDP induction properties, AP–EPSP sequences lead to supralinear summation of spine [Ca2+] transients. Furthermore, afterdepolarizations (ADPs) following APs efficiently propagate into dendrites of CA3 pyramidal neurons, and EPSPs summate with dendritic ADPs. In autoassociative network models, storage and recall are more robust with symmetric than with asymmetric STDP rules. Thus, a specialized STDP induction rule allows reliable storage and recall of information in the hippocampal CA3 network.}, author = {Mishra, Rajiv Kumar and Kim, Sooyun and Guzmán, José and Jonas, Peter M}, journal = {Nature Communications}, publisher = {Nature Publishing Group}, title = {{Symmetric spike timing-dependent plasticity at CA3–CA3 synapses optimizes storage and recall in autoassociative networks}}, doi = {10.1038/ncomms11552}, volume = {7}, year = {2016}, } @article{1435, abstract = {ATP released from neurons and astrocytes during neuronal activity or under pathophysiological circumstances is able to influence information flow in neuronal circuits by activation of ionotropic P2X and metabotropic P2Y receptors and subsequent modulation of cellular excitability, synaptic strength, and plasticity. In the present paper we review cellular and network effects of P2Y receptors in the brain. We show that P2Y receptors inhibit the release of neurotransmitters, modulate voltage- and ligand-gated ion channels, and differentially influence the induction of synaptic plasticity in the prefrontal cortex, hippocampus, and cerebellum. The findings discussed here may explain how P2Y1 receptor activation during brain injury, hypoxia, inflammation, schizophrenia, or Alzheimer's disease leads to an impairment of cognitive processes. Hence, it is suggested that the blockade of P2Y1 receptors may have therapeutic potential against cognitive disturbances in these states.}, author = {Guzmán, José and Gerevich, Zoltan}, journal = {Neural Plasticity}, publisher = {Hindawi Publishing Corporation}, title = {{P2Y receptors in synaptic transmission and plasticity: Therapeutic potential in cognitive dysfunction}}, doi = {10.1155/2016/1207393}, volume = {2016}, year = {2016}, } @article{1350, abstract = {The hippocampal CA3 region plays a key role in learning and memory. Recurrent CA3–CA3 synapses are thought to be the subcellular substrate of pattern completion. However, the synaptic mechanisms of this network computation remain enigmatic. To investigate these mechanisms, we combined functional connectivity analysis with network modeling. Simultaneous recording fromup to eight CA3 pyramidal neurons revealed that connectivity was sparse, spatially uniform, and highly enriched in disynaptic motifs (reciprocal, convergence,divergence, and chain motifs). Unitary connections were composed of one or two synaptic contacts, suggesting efficient use of postsynaptic space. Real-size modeling indicated that CA3 networks with sparse connectivity, disynaptic motifs, and single-contact connections robustly generated pattern completion.Thus, macro- and microconnectivity contribute to efficient memory storage and retrieval in hippocampal networks.}, author = {Guzmán, José and Schlögl, Alois and Frotscher, Michael and Jonas, Peter M}, journal = {Science}, number = {6304}, pages = {1117 -- 1123}, publisher = {American Association for the Advancement of Science}, title = {{Synaptic mechanisms of pattern completion in the hippocampal CA3 network}}, doi = {10.1126/science.aaf1836}, volume = {353}, year = {2016}, } @article{2230, abstract = {Intracellular electrophysiological recordings provide crucial insights into elementary neuronal signals such as action potentials and synaptic currents. Analyzing and interpreting these signals is essential for a quantitative understanding of neuronal information processing, and requires both fast data visualization and ready access to complex analysis routines. To achieve this goal, we have developed Stimfit, a free software package for cellular neurophysiology with a Python scripting interface and a built-in Python shell. The program supports most standard file formats for cellular neurophysiology and other biomedical signals through the Biosig library. To quantify and interpret the activity of single neurons and communication between neurons, the program includes algorithms to characterize the kinetics of presynaptic action potentials and postsynaptic currents, estimate latencies between pre- and postsynaptic events, and detect spontaneously occurring events. We validate and benchmark these algorithms, give estimation errors, and provide sample use cases, showing that Stimfit represents an efficient, accessible and extensible way to accurately analyze and interpret neuronal signals.}, author = {Guzmán, José and Schlögl, Alois and Schmidt Hieber, Christoph}, issn = {16625196}, journal = {Frontiers in Neuroinformatics}, number = {FEB}, publisher = {Frontiers Research Foundation}, title = {{Stimfit: Quantifying electrophysiological data with Python}}, doi = {10.3389/fninf.2014.00016}, volume = {8}, year = {2014}, } @article{3258, abstract = {CA3 pyramidal neurons are important for memory formation and pattern completion in the hippocampal network. It is generally thought that proximal synapses from the mossy fibers activate these neurons most efficiently, whereas distal inputs from the perforant path have a weaker modulatory influence. We used confocally targeted patch-clamp recording from dendrites and axons to map the activation of rat CA3 pyramidal neurons at the subcellular level. Our results reveal two distinct dendritic domains. In the proximal domain, action potentials initiated in the axon backpropagate actively with large amplitude and fast time course. In the distal domain, Na+ channel–mediated dendritic spikes are efficiently initiated by waveforms mimicking synaptic events. CA3 pyramidal neuron dendrites showed a high Na+-to-K+ conductance density ratio, providing ideal conditions for active backpropagation and dendritic spike initiation. Dendritic spikes may enhance the computational power of CA3 pyramidal neurons in the hippocampal network.}, author = {Kim, Sooyun and Guzmán, José and Hu, Hua and Jonas, Peter M}, issn = {1546-1726}, journal = {Nature Neuroscience}, number = {4}, pages = {600 -- 606}, publisher = {Nature Publishing Group}, title = {{Active dendrites support efficient initiation of dendritic spikes in hippocampal CA3 pyramidal neurons}}, doi = {10.1038/nn.3060}, volume = {15}, year = {2012}, } @article{3718, abstract = {Long-term depression (LTD) is a form of synaptic plasticity that may contribute to information storage in the central nervous system. Here we report that LTD can be elicited in layer 5 pyramidal neurons of the rat prefrontal cortex by pairing low frequency stimulation with a modest postsynaptic depolarization. The induction of LTD required the activation of both metabotropic glutamate receptors of the mGlu1 subtype and voltage-sensitive Ca(2+) channels (VSCCs) of the T/R, P/Q and N types, leading to the stimulation of intracellular inositol trisphosphate (IP3) receptors by IP3 and Ca(2+). The subsequent release of Ca(2+) from intracellular stores activated the protein phosphatase cascade involving calcineurin and protein phosphatase 1. The activation of purinergic P2Y(1) receptors blocked LTD. This effect was prevented by P2Y(1) receptor antagonists and was absent in mice lacking P2Y(1) but not P2Y(2) receptors. We also found that activation of P2Y(1) receptors inhibits Ca(2+) transients via VSCCs in the apical dendrites and spines of pyramidal neurons. In addition, we show that the release of ATP under hypoxia is able to inhibit LTD by acting on postsynaptic P2Y(1) receptors. In conclusion, these data suggest that the reduction of Ca(2+) influx via VSCCs caused by the activation of P2Y(1) receptors by ATP is the possible mechanism for the inhibition of LTD in prefrontal cortex.}, author = {Guzmán, José and Schmidt, Hartmut and Franke, Heike and Krügel, Ute and Eilers, Jens and Illes, Peter and Gerevich, Zoltan}, journal = {Neuropharmacology}, number = {6}, pages = {406 -- 415}, publisher = {Elsevier}, title = {{P2Y1 receptors inhibit long-term depression in the prefrontal cortex.}}, doi = {10.1016/j.neuropharm.2010.05.013}, volume = {59}, year = {2010}, } @article{3832, abstract = {A recent paper by von Engelhardt et al. identifies a novel auxiliary subunit of native AMPARs, termedCKAMP44. Unlike other auxiliary subunits, CKAMP44 accelerates desensitization and prolongs recovery from desensitization. CKAMP44 is highly expressed in hippocampal dentate gyrus granule cells and decreases the paired-pulse ratio at perforant path input synapses. Thus, both principal and auxiliary AMPAR subunits control the time course of signaling at glutamatergic synapses.}, author = {Guzmán, José and Jonas, Peter M}, journal = {Neuron}, number = {1}, pages = {8 -- 10}, publisher = {Elsevier}, title = {{Beyond TARPs: The growing list of auxiliary AMPAR subunits}}, doi = {10.1016/j.neuron.2010.04.003}, volume = {66}, year = {2010}, } @article{3720, author = {Guzmán, José and Gerevich, Zoltan and Hengstler, Jan and Illes, Peter and Kleemann, Werner}, journal = {Synapse}, number = {4}, pages = {235 -- 238}, publisher = {Wiley}, title = {{P2Y1 receptors inhibit both strength and plasticity of glutamatergic synaptic neurotransmission in the rat prefrontal cortex.}}, doi = {10.1002/syn.20177}, volume = {57}, year = {2005}, }