Research ArticleResearch Article: New Research, Neuronal Excitability

Recurring Cholinergic Inputs Induce Local Hippocampal Plasticity through Feedforward Disinhibition

Inês Guerreiro, Zhenglin Gu, Jerrel L. Yakel and Boris S. Gutkin
eNeuro 26 August 2022, 9 (5) ENEURO.0389-21.2022; https://doi.org/10.1523/ENEURO.0389-21.2022

Article Figures & Data

Figures

  • Figure 1.
    Figure 1.

    Disynaptic disinhibition circuit for nAChR-modulated long-term plasticity in the CA1. A, Simplified wiring diagram of an interneuron network that mediates feedforward inhibition in the CA1 region of the hippocampus. Activation of the SC pathway leads to the activation of CA1 pyramidal cell dendrites and s.r. interneurons, which provide feedforward inhibition onto the pyramidal cell. Cholinergic activation of OLMα2 interneurons in s.o. leads to the inhibition of the s.r. interneurons, counteracting SC feedforward inhibition (Leão et al., 2012). B, Minimal network to investigate plasticity induced by the pairing of cholinergic and SC activation. Glutamate activates postsynaptic AMPARs and NMDARs at the pyramidal cell ED and postsynaptic AMPARs at I-cells, which in turn provide feedforward inhibition onto ED by activating postsynaptic GABAARs. Cholinergic inputs act on presynaptic α7 nAChRs of O-cells, which results in GABA release of the O-cells that it is going to bind to postsynaptic GABAARs of the I-cell.

  • Figure 2.
    Figure 2.

    Cholinergic activation of OLM interneurons potentiates SC-evoked EPSCs. A, Scheme of in vitro induction of cholinergic pairing-induced hippocampal synaptic plasticity. EPSCs were recorded from CA1 pyramidal neurons. Cholinergic neurons were activated via channelrhodopsin-2 that was specifically expressed in ChAT-positive neurons. The SC pathway was activated by a stimulating electrode. Adapted from the study by Gu et al. (2017). B, Scheme of the minimal network used to study the role of cholinergic inputs in the potentiation of SC-evoked EPSCs. Glutamatergic inputs activate the pyramidal cell ED and the fast-spiking I-cell that projects to it. Square pulses of ACh activate the O-cell during the copairing period. The neural response of O-cell, I-cell, and ED when the system receives one pulse of glutamate paired or not with ACh is shown in Extended Data Figure 2-1. The release of GABA from the O-cells is calculated using the simplified model described by Equation 16. The Extended Data Figure 2-2 shows that the simplified neurotransmitter release model results in a similar synaptic activation function as the detailed model described in the study by Destexhe et al. (1998). Different ACh synaptic profiles are explored in Extended Data Figure 2-3. C, Normalized SC-evoked EPSC responses from CA1 pyramidal neurons showing that the enhancement of EPSCs was impaired in hippocampal slices from mice with selective α7 nAChR knockout in OLMα2 interneurons. Adapted from the study by Gu et al. (2020). D, Numerical simulation of normalized EPSC amplitude when glutamatergic inputs acting on the I-cell and ED are paired with cholinergic inputs acting on the O-cell (from t = 10 min to t = 18 min). The EPSCs are calculated as the sum of postsynaptic AMPA and NMDA currents, IAMPA and INMDA, resulting from 10 simulations with white noise on the ED membrane potential. Noisy membrane potentials of the O-cells and I-cells that induce spontaneous spiking are considered in Extended Data Figure 2-4. Normalization of the results was calculated according with the expression (100 + (EPSC – EPSCmin) · (150–100))/(EPSCmax – EPSCmin). Inset, Concentration of GABA released from fast-spiking interneurons (I), calculated according to Equation 15 (see Materials and Methods). E, Normalized SC-evoked EPSC responses from CA1 pyramidal neurons showing that enhancement of EPSCs during a copairing period of 5 min. F, Numerical simulation of normalized EPSC amplitude when glutamatergic inputs acting on the I-cell and ED are paired with cholinergic inputs acting on the O-cell (from t = 10 min to t = 15 min).

  • Figure 3.
    Figure 3.

    Copairing temporal parameters determines the duration and polarity of synaptic plasticity: relative timing among cholinergic and glutamatergic stimulation, the extent of the copairing period, and the frequency of stimulation (model results). A, Synaptic strength transient duration is proportional to the extent of the pairing period. Here, the transient duration is defined as the time it takes the EPSC to go back to baseline after copairing is over. The I-cell and ED receive a pulse of glutamate per minute. During the copairing period, the O-cell receives a pulse of ACh per minute, 100 ms before the glutamate pulses. B, Synaptic strength transient duration is proportional to the ACh and glutamate pulses frequency during the copairing period. Before and after the copairing period, the I-cell and ED receive a pulse of glutamate per minute. During the copairing period (4 min), the frequency changes to 1/20, 1/60, or 1/30 s, and the O-cell receives a pulse of ACh 100 ms before the glutamate pulses with the same frequency. C, Relative pairing timing of single pulses provides a window of opportunity for plasticity. If glutamatergic inputs are administered within 10.4 ms < Δt < 131.1 ms, the ED excitatory synapse is potentiated. If glutamatergic inputs are administered within −19.9 ms < Δt < 10.4 ms or 10.4 ms < Δt < 131.1 ms, depression is induced. The change in the AMPAR conductance Δg¯ AMPA is measured 60 ms after one pairing. The relative time between cholinergic and glutamatergic activation of the network determines how efficiently the O-cells suppress spiking of the I-cells, as shown in Extended Data Figure 3-1. If noise is added to the membrane potential of ED, the window of depression and potentiation is not as well defined, as shown in Extended Data Figure 3-2. D, Pairing multiple pulses of glutamate and ACh can change the window of opportunity for plasticity. Two pulses of glutamate and ACh with a frequency of 2 Hz are paired. If glutamatergic inputs arrive within −19.9 ms < Δt < 10.9 ms or 149.9 ms < Δt < 320 ms of the cholinergic inputs, depression is induced. If glutamatergic inputs are administered within 10.9 ms < Δt < 149.9 ms, the ED excitatory synapse is potentiated. The change in the AMPAR conductance Δg¯ AMPA is measured 60 ms after one pairing. The pairing times of cholinergic and SC inputs found by Gu and Yakel (2011) to induce short-term depression and long-term potentiation at the SC–CA1 synapse (indicated with the red cross) are within our range of depression and potentiation.

  • Figure 4.
    Figure 4.

    Disinhibition of CA1 pyramidal cell facilitates the induction of hippocampal synaptic plasticity. A, Scheme of in vitro induction of hippocampal synaptic plasticity through concurrent Sst inhibition. EPSCs were recorded from CA1 pyramidal neurons. Sst neurons were inhibited via eNpHR that was specifically expressed in Sst-positive neurons. The SC pathway was activated by a stimulating electrode. B, Schematic representation of a CA1 pyramidal neuron dendritic compartment ED with postsynaptic GABAA, AMPA, and NMDA receptors used to study the disinhibitory mechanisms for induction of plasticity at the SC–CA1 excitatory synapse. The dendritic compartment of the pyramidal cell receives one pulse of both glutamate and GABA per minute, except during the disinhibition period, where it only receives pulses of glutamate. The GABA pulse, presumably from the I-cell, is described by a square function with similar amplitude and duration as the glutamate pulse (see Materials and Methods; Extended Data Figs. 4-1, 4-2, justification). Glutamate binds to the excitatory AMPA and NMDA receptors, while GABA binds to the inhibitory GABAA receptor. The synaptic currents and membrane potential of ED when a pulse of glutamate is paired (or not) with a pulse of GABA are shown in Extended Data Figure 4-3. C, Experimental measurements showing the effects of inhibition of Sst and OLMα2 interneurons in s.o. on SC-evoked EPSCs (n = 5 slices for each group). Inhibition of Sst interneurons from t = 5 min to t = 10 min enhanced the SC-evoked EPSC amplitude of the CA1 pyramidal cell, followed by a return to the baseline after the inhibition period (blue line). Inhibition of Sst interneurons from t = 5 min to t = 13 min increased SC-evoked amplitude EPSCs, which remained potentiated after the inhibition period (orange line). D, Numerical simulation of normalized EPSCs of ED for a disinhibition period of 5 min (from t = 5 min to t = 10 min) and 8 min (from t = 5 min to t = 13 min). Normalization of the results was calculated according with the expression (100 + (EPSC – EPSCmin) · (150–100))/(EPSCmax – EPSCmin).

  • Figure 5.
    Figure 5.

    Calcium dynamic is key for the induction of synaptic plasticity. A, Time course of maximal AMPAR conductance, g¯ AMPA, when the dendritic compartment is disinhibited for a short period (from t = 5 min to t = 10 min). The maximal AMPAR conductance increases from its initial value g¯ AMPA = 4 nS to g¯ AMPA = 6.9 nS during the disinhibition period (gray area). B, Time course of g¯ AMPA when the dendritic compartment is disinhibited for a long period (from t = 5 min to t = 13 min). It increases from g¯ AMPA = 4 nS to g¯ AMPA = 8.83 nS during the disinhibition period. Changes in the AMPAR conductance, g¯ AMPA, are described by Equation 22. C, Time course of intracellular calcium concentration when ED is disinhibited for a short period (from t = 5 min to t = 10 min), where θ↓ is the depression onset, and θ↑ is the potentiation onset. D, Time course of intracellular calcium concentration when the dendritic compartment is disinhibited for a long period (from t = 5 min to t = 13 min). The calcium dynamics is described by Equation 25 (see Materials and Methods). E, Trajectories of the system in the g¯ AMPA–Ca plane when a pulse of glutamate is paired with a pulse of GABA for g¯ AMPA = 6.9 nS and g¯ AMPA = 8.83 nS, where θpot is the potentiation threshold as defined in the Results section. F, Changes in the maximal AMPAR conductance, Δg¯ AMPA, as a function of the amplitude of intracellular calcium pulse, Camax. Each point of the graph was obtained by submitting ED to a glutamate pulse for different initial values of g¯ AMPA. This induced different depolarization levels and, consequently, different activation levels of NMDARs and calcium pulses of different amplitudes.

  • Figure 6.
    Figure 6.

    The weighted ratio (A↑/A↓)w can accurately be used as a predictor of induction of depression or potentiation. The depression and potentiation areas A↓ and A↑ are as defined in Extended Data Figure 6-1. A, Different values of g¯ AMPA evoke different levels of depolarization and, consequently, different intracellular calcium concentrations. For a weighted ratio between the calcium area of AMPAR insertion and removal at<3.00, depression is induced. For a value >3.00, potentiation is induced. B, By adding a second source of calcium that becomes activated at t = 80 ms, it is possible to have situations where the calcium never crosses the potentiation threshold θpot but potentiation is induced. The (A↑/A↓)w accurately identifies these cases as potentiation. In these numerical simulations, ED receives a pulse of glutamate followed by a pulse of GABA 2 ms after, each with an amplitude of 1 mm and a duration of 1 ms.

  • Figure 7.
    Figure 7.

    Amplitude of GABA pulse, GABAmax, and relative time between GABA and glutamate pulses, Δt(GABA−Glu), control the direction and efficiency of the induction of synaptic plasticity. A, Depression and potentiation regions for g¯ AMPA = 4 nS. This is the maximal conductance value of the AMPAR used in our simulations before the disinhibition period starts. B, Depression and potentiation regions forg¯ AMPA = 6.9 nS, which represents the state of phosphorylation of the AMPAR at the end of the short disinhibition period. C, Depression and potentiation regions for g¯ AMPA = 8.83 nS, which is the state of phosphorylation of the AMPAR at the end of the long disinhibition period. For each plot in A, B, and C, we pair one pulse of glutamate (with a concentration of 1 mm and 1 ms of duration) with one pulse of GABA with a duration of 1 ms and varying concentrations and initial time, and measure the resultant change in g¯ AMPA for each case.

  • Figure 8.
    Figure 8.

    Scheme of the cholinergic and disinhibitory mechanisms that drive SC–CA1 potentiation. A, Glutamatergic activation of I-cells lead to spiking activity and consequent GABA release. Subsequently, glutamate inputs acting on ED evoke an EPSP mediated by AMPAR immediately followed by an IPSP-mediated GABA acting on GABAA receptors. B, Cholinergic activation of α7 nAChR on OLM interneuron initiates a CICR process mediated by calcium internal stores (IS). This result in GABA release that inhibits the I-cell. The dendritic compartment does not receive GABAergic inhibition. The dendritic compartment can depolarize enough—and remain depolarized for long enough—to relieve Mg2+ block from NMDA receptors, allowing calcium to permeate through the receptor channel. C, CICR mechanism. The entry of calcium through α7 nAChRs induces calcium release form internal stores by activating IP3 receptors.

Tables

  • Table 1

    Parameters of pyramidal cell, OLM interneuron, and fast-spiking interneuron dynamics

    ParameterValue
    O-cells
     Cm100 pF
     gleak50 nS
     Eleak−70 mV
     g¯K 1100 nS
     EK−90 mV
     g¯Na 5200 nS
     ENa55 mV
     g¯p 50 nS
     g¯h 145 nS
     Eh−20 mV
    I-cells
     Cm100 pF
     gleak10 nS
     Eleak−67 mV
     g¯K 8000 nS
     EK−100 mV
     g¯Na 10,000 nS
     ENa50 mV
    ED
     Cm100 pF
     gleak1 nS
     Eleak−68 mV

    • All the parameter values and expressions here described were taken from the study by Rotstein et al. (2005), considering a surface area of 1 × 10−4 cm2, except for the reversal potential of the leakage current of the OLM, which was set to have the resting potential of the OLM cells at −60 mV, as reported in the study by Leão et al. (2012).

  • Table 2

    Parameter values of synaptic currents IAMPA, INMDA, IGABAA, and Iα7

    ParameterValueReference
    αA1.1 ms−1 mM−1Destexhe et al. (1998)
    βA0.19 ms−1Destexhe et al. (1998)
    g¯AMPA 7*, 4† nSAndrásfalvy et al. (2003)
    EA0 mVDestexhe et al. (1998)
    [Mg2+]1 mmDestexhe et al. (1998)
    αN0.072 ms−1 mM−1Destexhe et al. (1998)
    βN6.6 × 10−3 ms−1Destexhe et al. (1998)
    g¯N 25 nSAndrásfalvy et al. (2003)
    EN0 mVDestexhe et al. (1998)
    αG5 ms−1 mM−1Destexhe et al. (1998)
    βG0.18 ms−1Destexhe et al. (1998)
    g¯G 14*, 7† nSSchulz et al. (2018)
    EG−80 mVDestexhe et al. (1998)
    Eα70 mVCastro and Albuquerque (1995)
    g¯α7 3 nSLeão et al. (2012)
    EC5080 × 10–3 mmGraupner et al. (2013)
    τrα75 msGraupner et al. (2013)
    n1.73Graupner et al. (2013)
    Tmax1 mmDestexhe et al. (1998)
    Kp5 mVDestexhe et al. (1998)
    Vp2 mVDestexhe et al. (1998)
    K(Ca)p1 × 10–6 mmMaterials and Methods
    Cap4 × 10–5 mmMaterials and Methods

    • *Values refer to the conductance of postsynaptic channels on the fast-spiking interneurons.

    • †Values refer to the conductances of the dendritic compartment ED.

  • Table 3

    Parameter values for calcium dynamics and synaptic plasticity

    ParameterValueReference
    σ0.0040 ms−1Materials and Methods
    P11.5e-6Shouval et al. (2002)
    P2P1 × 10−4Shouval et al. (2002)
    P313Shouval et al. (2002)
    P41Shouval et al. (2002)
    θ↑0.34 μmMaterials and Methods
    θ↓0.31 μmMaterials and Methods
    γ↑0.0687,* 0.0699† nS/msMaterials and Methods
    γ↓0.0375 nS/msMaterials and Methods
    α0.1Burnashev et al. (1995)
    ξ0.006,* 0.045† μm/(ms/pA)Sabatini et al. (2002)
    τCa12 msSabatini et al. (2002)
    ξ′2.1 × 10–6 mm/(ms pA)Materials and Methods
    α′0.05Vernino et al. (1994)
    τ10 msMaterials and Methods
    kd2 × 10–4 mmMaterials and Methods

    • *Values used to reproduce Figures 2 and 3.

    • †Values used to reproduce the remaining figures.

Extended Data

  • Figure 2-1

    A, Before copairing, the α7 nAChR at OLM is not activated, and the OLM cell is not depolarized (dashed line). During copairing, OLM receives a square pulse of ACh with an amplitude of 1 mm and 5 ms of duration (solid line). The OLM is weakly depolarized (solid line). B, Before copairing, there are no changes in the intracellular calcium concentration Cai (dashed line). During copairing, calcium through α7 nAChR triggers CICR mechanisms that increase the intracellular calcium concentration of the O-cell (solid line). C, An increase in intracellular calcium results in GABA release from the O-cell (GABAO). The neurotransmitter concentration is calculated according to the simplified model (solid line). D, The release of GABAO during copairing suppresses spiking of the I-cell evoked by glutamatergic activation (solid line). E, Before copairing, the spiking of the I-cell is not suppressed and inhibits ED, which cannot depolarize a lot (dashed line). During copairing, ED does not receive inhibition, only excitation from glutamatergic stimulation, and it depolarizes (solid line). Download Figure 2-1, TIF file.

  • Figure 2-2

    Simplified neurotransmitter release model. A, Square calcium pulse of 0.10 μm amplitude and 1 ms of duration. B, GABA concentration elicited by a calcium pulse of 0.10 μm amplitude and 1 ms of duration computed using the detailed model of transmitter release described in the study by Destexhe et al. (1998) and using Equation 16. C, Both models of GABA concentration elicit similar synaptic activation functions, rG (described by Eq. 14 with αG = 5 ms/m and βG = 0.18 ms). Download Figure 2-2, TIF file.

  • Figure 2-3

    Not much is known about the ACh profile in the synaptic cleft upon release from cholinergic neurons; more specifically, not much is known about the time it takes for ACh to be broken down by the cholinesterase and therefore, how long it is available to bind to the cholinergic receptors. We consider the observations made by Gu and Yakel (2011) that pairing cholinergic inputs 10 ms prior to SC stimulation induces depression of the SC–CA1 synapse, while if the cholinergic inputs are activated 100 ms prior to SC stimulation, potentiation is induced. A–D, A square pulse of ACh followed by a pulse of glutamate 10 and 100 ms after will induce, respectively, depression or potentiation if the duration of the ACh pulse is equal or greater than the glutamate. E–H, If ACh is described by an α function with an instantaneous rise time; the smaller the amplitude of the ACh pulse, the longer the decay time needs to be for the results to agree with those in the study by Gu and Yakel (2011). That being said, we model ACh as a square pulse with a duration of 5 ms and concentration of 1 mm, similar to glutamate. Please note that the decay and duration times, as well as the amplitude, of both the ACh and glutamate pulses serve merely as a guide to what types of neurotransmitter profiles we should consider. They are qualitative, and not quantitative, predictions of the synaptic profile of ACh. Copairing of one pulse of ACh (with different synaptic profiles) with one square pulse of glutamate (with a duration of 5 ms and amplitude of 1 mm) for a relative pairing time Δt of 10 and 100 ms. A, Left, One square pulse of ACh with a duration of 1 ms and concentration of 0.5 mm followed 10 ms after by a square pulse of glutamate produces no changes in the maximal conductance of AMPAR,g¯AMPA . Right, Similarly, If the pulse of glutamate arrives 100 ms after, no changes are induced. B, Left, One square pulse of ACh with a duration of 5 ms and a concentration of 0.5 mm followed 10 ms after by a pulse of glutamate decreases the maximal conductance of AMPAR,g¯AMPA . Right, If the pulse of glutamate arrives 100 ms after, potentiation is induced. C, Left, One square pulse of ACh with a duration of 1 ms and concentration of 1 mm followed 10 ms after by a square pulse of glutamate produces no changes in the maximal conductance of AMPAR,g¯AMPA . Right, Similarly, if the pulse of glutamate arrives 100 ms after, no changes are induced. D, Left, One square pulse of ACh followed 10 ms after by a pulse of glutamate with the same characteristics (duration of 5 ms and 1 mm concentration) decrease the maximal conductance of AMPAR,g¯AMPA . Right, If the pulse of glutamate arrives 100 ms after, potentiation is induced. E, Left, One pulse of ACh with an amplitude of 0.39 mm and a decay time constant of 1 ms followed 10 ms after by a square pulse of glutamate induces no changes ing¯AMPA . Right, Similarly, if the pulse of glutamate arrives 100 ms after, no changes are induced. F, Left, One pulse of ACh with an amplitude of 0.39 mm and a decay time constant of 4 ms followed 10 ms later by a square pulse of glutamate depressesg¯AMPA . Right, If the pulse of glutamate arrives 100 ms after, potentiation is induced. G, Left, One pulse of ACh with an amplitude of 1 mm and a decay time constant of 1 ms followed 10 ms later by a square pulse of glutamate provokes a decrease ing¯AMPA . Right, If the pulse of glutamate arrives 100 ms after, no changes are induced. H, Left, One pulse of ACh with an amplitude of 1 mm and a decay time constant of 4 ms followed 10 ms later by a square pulse of glutamate depressesg¯AMPA . Right, If the pulse of glutamate arrives 100 ms after, potentiation is induced. Download Figure 2-3, TIF file.

  • Figure 2-4

    A, Time evolution of the membrane potential of the O-cell, I-cell, and ED with noisy background currents when cholinergic inputs are paired with SC inputs, and resultant EPSCs. B, Mean trace of normalized EPSCs after 10 simulations. Adding a noisy background current to the O-cell and I-cell induces spontaneous spiking. Copairing cholinergic and glutamatergic inputs from t = 10 min to t = 18 min induces potentiation of the pyramidal cell EPSC. The O-cell releases GABA when the intracellular calcium concentration is high enough (Eq. 16) and when the cell spikes (Eq. 15). All the remaining parameters are identical to the ones used to produce Figure 6. Noise was incorporated by adding a stochastic termdtζ , where ζ is a random Gaussian variable with a mean of μ = 0 and an SD of σ (=1.1, 0.1, and 0.2 for the O-cells, I-cells, and ED, respectively), to the Euler equations describing the Vx. Normalization of the results was calculated according with the expression (100 + (EPSC – EPSCmin) · (150 – 100))/(EPSCmax – EPSCmin). Download Figure 2-4, TIF file.

  • Figure 3-1

    Tightly timed pairing of cholinergic to glutamatergic inputs can cancel the I-cell feedforward inhibition. For Δt = –30 ms (Region I), a pulse of glutamate activates the I-cell. When the OLM cell receives a pulse of ACh 30 ms after and releases GABA, the I-cell already emitted two spikes and inhibit ED, no plasticity is induced. For Δt =0 ms (Region II), the I-cell and OLM receive a pulse of glutamate and ACh, respectively, simultaneously. Due to its fast dynamics, the I-cell manages to emit one spike before being inhibited by GABAO. The I-cell inhibits ED only moderately and depression is induced. For Δt = 100 ms (Region III), OLM receives an ACh pulse at t = 0 ms and releases GABAO into the I-cell. When the I-cell receives glutamate 100 ms after, it is hyperpolarized and cannot spike; potentiation is induced. For Δt = 150 ms (Region IV), the hyperpolarization of the I-cell is starting to wear off and the cell manages to emit one spike, sending moderate inhibition to ED; depression is induced. For Δt = 300 ms (Region V), the I-cell can emit two spikes when it receives glutamate 300 ms after cholinergic activation; no plasticity is induced. Download Figure 3-1, TIF file.

  • Figure 3-2

    Mean relative pairing timing of single pulses of ACh and glutamate with noisy membrane potential of ED after 10 simulations. Noise was incorporated by adding a stochastic termdtζ , where ζ a random Gaussian variable with a mean of μ = 0 and an SD of σ = 0 to the Euler equations describing the VED. The mean trace of normalized EPSCs after 10 simulations. When a noisy membrane potential is considered, the transition between the depression and potentiation windows is less sharp (Fig. 3C, comparison). Download Figure 3-2, TIF file.

  • Figure 4-1

    I-cell GABA release evoked can be approximated by a square function. A, Membrane potential of the I-cell when it receives two pulses of glutamate (with an amplitude of 1 mm and a duration of 3 ms) with a frequency of 0.2 ms. B, GABA release from I-cell when it receives the action potentials described in A, calculated using Equation 15. Download Figure 4-1, TIF file.

  • Figure 4-2

    Sets of parameters that qualitatively reproduce Figure 4D. A, Numerical simulations of normalized EPSCs of ED for varying the amplitude and duration of the glutamate and GABA pulses. B, Parameters of maximum depression (γ↓), maximum potentiation (γ↑), synaptic plasticity decay constant (σ), and potentiation threshold (θ↑) from the shaded areas qualitatively reproduce Figure 4D. The quality of EPSC traces generated with different parameters was evaluated by measuring the relative variations of EPSC amplitude (in non-normalized and non-noisy simulations) from 5 to 30 min after the disinhibition period was over for a 5 and 8 min disinhibition period. Simulations were the variation (percentage of plasticity) was<4% and >22% for the long and short disinhibition periods, respectively, and were considered to conserve the shape of the experimental EPSC trace. This ensures that, for the long disinhibition period, the EPSCs do not decay faster than the experimental EPSCs observed, or slower, for the case of the short period, and therefore have a similar shape. Experimental measures describe the relative increase in EPSC amplitude from the baseline value to 5 min (%(5-B)) and 30 min (%(30-B)) after the disinhibition period is over (see the Results section for the values of %(5-B) and %(30-B) for 5 and 8 min disinhibition periods). This allows us to derive the relative changes from 5 to 30 min [%(30-5) = (%(30-B) – %(5-B))/(100 + %(5-B)) × 100]. By considering the relative changes between 5 and 30 min after the disinhibition period instead of the changes between the baseline and 5 and 30 min, we decrease the number of conditions to evaluate and the computational cost of performing the parameter exploration. The gray and beige areas represent the parameter space where both conditions are met. Note that increasing the synaptic plasticity decay constant σ decreases the robustness of the model to variations of the maximum depression and potentiation, γ↓ and γ↑ (B, beige area). On the other hand, increasing the potentiation threshold θ↑ changes the robustness of the model to changes in γ↑. As θ↑ approaches the depression threshold θ↓ or the maximum calcium amplitude Camax, the robustness in γ↑ decreases. b1, Gray and beige area: parameter space γ↓ – γ↑ where the percentage of plasticity is<4% for an 8 min disinhibition period and >22% for a 5 min disinhibition period for σ = 0.004 and σ = 0.005, respectively. b2, Relative variation of EPSC amplitude from 5 to 30 min after disinhibition period (percentage plasticity) for a disinhibition period of 5 min and  σ = 0.005 for different values of γ↓ and γ↑. b3, Relative variation of EPSC amplitude from 5 to 30 min after disinhibition period (percentage plasticity) for a disinhibition period of 8 min and σ = 0.005 for different values of γ↓ and γ↑. b4, Relative variation of EPSC amplitude from 5 to 30 min after disinhibition period (percentage plasticity) for a disinhibition period of 5 min and σ = 0.004 for different values of γ↓ and γ↑. b5, Relative variation of EPSC amplitude from 5 to 30 min after disinhibition period (percentage plasticity) for a disinhibition period of 8 min and  σ = 0.004 for different values of γ↓ and γ↑. b6, Gray area: parameter region γ↑ – θ↑ where the percentage plasticity is<4% for an 8 min disinhibition period and >22% for a 5 min disinhibition period for σ = 0.004. b7, Relative variation of EPSC amplitude from 5 to 30 min after the disinhibition period (percentage plasticity) for a disinhibition period of 5 min for different values of γ↑ and θ↑. b8, Relative variation of EPSC amplitude from 5 to 30 min after the disinhibition period (percentage plasticity) for a disinhibition period of 8 min for different values of γ↑ and θ↑. b9, Numerical simulations of normalized EPSCs of ED for different points of the parameter space γ↓ – γ↑ and γ↑ – θ↑. Download Figure 4-2, TIF file.

  • Figure 4-3

    A square GABA pulse with 1 mm amplitude and 1 ms of duration evokes a GABAA current at ED, and decrease NMDA current and depolarization. A, One square pulse of GABA with 1 mm amplitude and 1 ms of duration evokes an inhibitory GABAA current at ED (IGABAA). B, When ED receives a GABA square pulse, glutamatergic activation of ED only evokes a depolarization of –63.56 mV (dashed line). C, When ED does not receive GABA inputs, glutamate inputs evoke a depolarization of –58.25 mV (solid line). When ED does not receive GABA inputs, glutamatergic activation evokes a NMDA current of 7.90 pA (solid line). When it receives a GABA square pulse, the evoked NMDA current is 6.75 pA (dashed line). Download Figure 4-3, TIF file.

  • Figure 6-1

    Area of potentiation (orange) and area of depression (gray) considered to calculate the (A↑/A↓)w. For the description of the labels, please refer to Figure 6 in the main text. From t0 to t1 and t2 to t3, calcium is above θ↓ and below θ↑. These regions constitute the area of depression A↓. From t1 to t2, calcium is above θ↑. This region constitutes the area of potentiation A↑. While the calcium concentration is above the depression onset θ↓ (but below the potentiation onset θ↑), the maximal conductance of the AMPARs g¯ AMPA is decreasing. On the other hand, when the calcium concentration is above θ↑,< g¯ AMPA is increasing. The induction of plasticity at the excitatory synapse depends on the net result of these changes of g¯ AMPA. The more time calcium spends above θ↑/θ↓, the more likely it is that potentiation/depression is induced at the synapse. Furthermore, the more time calcium spends above θ↑/θ↓, the bigger the area underneath the calcium curve in this region of insertion/removal of AMPARs. Therefore, the ratio between the area of insertion and the area of removal (A↑/A↓) can be used as a measure of induction of plasticity (Fig. 6, main text). There is an optimal ratio for which the decrease of g¯ AMPA resultant from time spent in the removal region and the increase of g¯ AMPA resultant from time spent in the insertion region will cancel each other and no plasticity is induced. If the ratio A↑/A↓ is below this value, depression is induced; if the ratio is above this value, potentiation is induced. The ratio A↑/A↓ is given by  ∫t1t2Ca dt∫t0t1Ca dt+ ∫t2t3Ca dt . Because the decrease and increase of g¯ AMPA is not the same in the whole removal and insertion region, we need to calculate the calcium integral weighted by the calcium-dependent learning rate η. The (A↑/A↓)w is then given by  ∫t1t2Ca.η dt∫t0t1Ca.η dt+ ∫t2t3Ca.η dt . To calculate (A↑/A↓)w, we use the trapezoidal rule to perform numerical integration of the potentiation and depression area. Download Figure 6-1, TIF file.

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eneuro: 9 (5)
eNeuro
Vol. 9, Issue 5
September/October 2022
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Recurring Cholinergic Inputs Induce Local Hippocampal Plasticity through Feedforward Disinhibition
Inês Guerreiro, Zhenglin Gu, Jerrel L. Yakel, Boris S. Gutkin
eNeuro 26 August 2022, 9 (5) ENEURO.0389-21.2022; DOI: 10.1523/ENEURO.0389-21.2022
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