Heterosynaptic metaplastic regulation of synaptic efficacy in CA1 pyramidal neurons of rat hippocampus

International audienceThe induction threshold, and the magnitude and direction of changes in synaptic plasticity may depend on the previous history of neuronal activity. This phenomenon, termed "metaplasticity," could play an important role in integration processes by coordinating the modulation of synapses. Although metaplasticity has been analyzed extensively, its underlying cellular mechanisms remain largely unknown. Using in vitro electrophysiological and computer simulation approaches, we investigated the contribution of the slow Ca 2؉-dependent afterhyperpolariza-tion (sAHP) in the metaplastic control of the induction of long-term potentiation (LTP) at convergent CA3-CA1 pyramidal neuron synapses. We report that classical conditioning protocols may lead to the simultaneous induction of a sustained homosynaptic LTP and a potentiation of the sAHP that endured Ϸ1 h. The sAHP potentiation dramatically altered the spike responses of the CA1 pyramidal neuron. Of particular interest was the reduction of the CA1 neuron excitability and, consequently, of the capacity of a nonpotentiated synaptic input to elicit spikes while the sAHP was potentiated. This reduction in excitability temporarily prevented nonpotentiated synaptic inputs to exhibit an LTP induced by presynaptic tetanization. This metaplasticity was strongly resistant to increases in the magnitude of synaptic tetanization protocols. We propose that this het-erosynaptic metaplasticity, mediated by intrinsic cellular mechanisms, triggered by brief periods of activity, and relying on changes of a slow Ca 2؉-activated K ؉ current, may contribute to adjusting the efficacy of synaptic connections and shaping network behavior to regulate integration processes

Bidirectional hebbian plasticity induced by low-frequency stimulationin basal dendrites of rat barrel cortex layer 5 pyramidal neurons

According to Hebb’s original hypothesis (Hebb,1949), synapses are reinforced when presynaptic activity triggers postsynaptic firing, resulting in long-term potentiation (LTP) of synaptic efficacy. Long-term depression (LTD) is a use-dependent decrease in synaptic strength that is thought to be due to synaptic in put causing a weak postsynaptic effect. Although the mechanisms that mediate long-term synaptic plasticity have been investigated for at least three decades not all question have as yet been answered. Therefore, we aimed at determining the mechanisms that generate LTP or LTD with the simplest possible protocol Low-frequency stimulation of basal dendrite inputs in Layer 5 pyramidal neurons of the rat barrel cortex induces LTP. This stimulation triggered an EPSP, an action potential (AP) burst, and a Ca2+ spike. The same stimulation induced LTD following manipulations that reduced the Ca2+ spike and Ca2+ signal or the AP burst. Low-frequency whisker deflections induced similar bidirectional plasticity of action potential evoked responses in anesthetized rats. These results suggest that both in vitro and in vivo similar mechanisms regulate the balance between LTP and LTD. This simple induction form of bidirectional hebbian plasticity could be present in the natural conditions to regulate the detection, flow, and storage of sensorimotor informationWork supported by “Ministerio de Ciencia y Tecnología y Ministerio de Ciencia e Innovación” grants (BFU2005-07486, BFU2008-03488, SAF2009-10339, BFU2011-23522, BFU2012-36107, BFU2013-43668-P and BFU2016-80802-P) and a “Comunidad Autónoma de Madrid” (GR/SAL/0877/2004) grant. Dr .D. Fernández de Sevilla was a post doctoral fellow at the “Instituto Cajal,” funded by GR/SAL/0877/2004 and a “Ministerio de Ciencia and Tecnología” grant (BFU2005-07486).He was subsequently supported by a Ramón y Cajal Contract and is now a Professor at the “Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid.” Dr. Andrea Diez was a doctoral fellow funded by the BFU2011-23522 grant and is now a post doctoral fellow funded by “Ministerio de Ciencia e Innovación” grant (BFU2013- 43741-P) at the “Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid.” N. Barros-Zulaica was a doctoral fellow funded by the BFU2012-36107 gran

Corrigendum: Bidirectional Hebbian Plasticity Induced by Low-Frequency Stimulation in Basal Dendrites of Rat Barrel Cortex Layer 5 Pyramidal Neurons

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Novel hyperpolarization-activated K+ current mediates anomalous rectification in crayfish muscle

The ionic current underlying anomalous rectification in opener muscle fibers of crayfish was studied under two-electrode voltage clamp. Opener muscle fibers showed a mean resting potential (RP) of -64.8 mV and an input resistance of 0.4 MΩ. Hyperpolarizing voltage command pulses from a holding potential (H) of -60 mV evoked an instantaneous voltage-independent linear current (I(L)) followed by a time- and voltage-dependent inward current (I(AB)) that reached a steady state within 500 msec. The reversal potential of I(AB) (E(AB)) was estimated from tail current amplitudes. At an extracellular K+ concentration ([K+](o)) of 5.4 mM the mean E(AB) was - 61.8 mV. E(AB) shifted toward positive potentials by 50.8 mV for a 10-fold increase in [K+](o). The conductance underlying I(AB) (G(AB)) increased sigmoidally with hyperpolarization, starting close to the RP, saturating at a G(AB,max) of about -140 mV, and showing a mean half-activation at -94.4 mV. The activation curve of G(AB) shifted 53.6 mV toward positive potentials with a 10-fold increase in [K+](o). G(AB,max) did not increase in raised [K+](o). The activation and deactivation kinetics of I(AB) were accurately described by single exponentials with similar time constants (< 100 msec). Time constants changed as an exponential function of the membrane potential. I(AB), its time course, G(AB), and E(AB) were not modified in the following conditions: (1) Na+- and Ca2+-free solutions, (2) intracellular EGTA, (3) extracellular (100 mM) or intracellular tetraethylammonium, (4) extracellular Cs+ (up to 50 mM), Rb+ (up to 10 mM), Ba2+ (13.5 mM), or Mn2+ (13.5 mM). However, low extracellular concentrations of Cd2+ or Zn2+ strongly and reversibly reduced both I(L) and I(AB). Therefore, we conclude that anomalous rectification in crayfish muscle is generated by a voltage- and time-dependent K+ current I(AB). This current displayed many electrophysiological and pharmacological characteristics that distinguished it from all others mediating anomalous rectification described previously.Peer Reviewe

Cd2+ regulation of the hyperpolarization-activated current I(AB) in crayfish muscle

The effects of Cd2+ on the hyperpolarization-activated K+-mediated current called I(AB) (Araque, A., and W. Buno. 1994. Journal of Neuroscience. 14:399-408.) were studied under two-electrode voltage-clamp in opener muscle fibers of the crayfish Procambarus clarkii. I(AB) was reversibly reduced by extracellular Cd2+ in a concentration-dependent manner, obeying the Hill equation with IC50 = 0.452 ± 0.045 mM and a Hill coefficient of 1 (determined from the maximal chord conductance of I(AB)). Cd2+ decreased the I(AB) conductance (G(AB)) and shifted its voltage dependence towards hyperpolarized potentials in a similar degree, without affecting the slope of the voltage dependence. The I(AB) activation time constant increased, whereas the I(AB) deactivation time constant was not modified by Cd2+. The I(AB) equilibrium potential (E(AB)) was unmodified by Cd2+, indicating that the selective permeability of I(AB) channels was not altered. I(AB) was unaffected by intracellular Cd2+. The Cd2+-regulation of I(AB) did not depend on [K+](o), and the effects of [K+](o), on I(AB) were unchanged by Cd2+, indicating that Cd2+ did not compete with K+. Therefore, Cd2+ probably bound to a different site to that involved in the K+ permeability pathway. We conclude that Cd2+ affected the gating of I(AB) channels, interfering with their opening but not with their closing mechanism. The results can be explained by a kinetic model in which the binding of Cd2+ to the I(AB) channels would stabilize the gating apparatus at its resting position, increasing the energy barrier for the transition from the closed to the open channel states.Peer Reviewe

The Theta Rhythm of the Hippocampus: From Neuronal and Circuit Mechanisms to Behavior

This review focuses on the neuronal and circuit mechanisms involved in the generation of the theta (θ) rhythm and of its participation in behavior. Data have accumulated indicating that θ arises from interactions between medial septum-diagonal band of Broca (MS-DbB) and intra-hippocampal circuits. The intrinsic properties of MS-DbB and hippocampal neurons have also been shown to play a key role in θ generation. A growing number of studies suggest that θ may represent a timing mechanism to temporally organize movement sequences, memory encoding, or planned trajectories for spatial navigation. To accomplish those functions, θ and gamma (γ) oscillations interact during the awake state and REM sleep, which are considered to be critical for learning and memory processes. Further, we discuss that the loss of this interaction is at the base of various neurophatological conditions.This work was supported by the Spanish Ministry of Science and Innovation Grant (PID2019-107809RB-I00)

Estradiol regulates the slow Ca2+-activated K+ current in hippocampal pyramidal neurons

The slow Ca2+-activated K+ current (SIAHP) was recorded in CA1 pyramidal neurons in hippocampal slices obtained from ovariectomized (OVX) or sham OVX (control) female rats. The SIAHP was significantly larger in cells from OVX rats than in cells from control rats. Superfusion with 5-100 nM 17β-estradiol (E2) caused a progressive decrease in the SIAHP in cells from OVX rats but not in cells from control rats. In slices from OVX rats injected with 10 μg of E2 24 and 48 hr before they were killed, superfusion with E2 did not modify the SIAHP. In neurons from OVX rats, but not in neurons from control rats, E2 significantly increased both the number of action potentials and the burst duration generated by depolarizing pulses. The inactive isomer 17α-estradiol had no effect. The impermeant protein conjugate E2-BSA was as effective as free E2 at decreasing the SIAHP. Ca2+ spikes were also depressed by E2 in neurons from OVX rats, but not in control rats. A decrease in the intracellular Ca2+ signal, correlating with the inhibition of the Ca2+ spike and SIAHP produced by E2, was observed only in neurons from OVX rats. Our results indicate that ovariectomy increases the SIAHP and depresses excitability, whereas bath application or priming with E2 decreases the SIAHP, thus promoting excitability. These effects of E2 on the SIAHP and excitability, which are stereospecific and presumably mediated by membrane-bound receptors, could contribute to the hormonal regulation of synaptic plasticity and epileptiform activity as well as to learning and cognitive abilities dependent on the function of hippocampal neural circuits.Peer Reviewe

Fast, persistent, Ca2+-dependent K+ current controls graded electrical activity in crayfish muscle

The early outward current in opener muscle fibres of crayfish (Procambarus clarkii) was studied using the two-electrode voltage-damp technique. This current was abolished in Ca2+-free and 5 mM Cd2+ solutions, and was blocked by extra- or intracellular tetraethylammonium, indicating that it was a Ca2+-dependent K+ current [I(K(Ca))]. I(K(Ca)) was voltage dependent, apamin insensitive and sensitive to charybdotoxin (CTX), which, in addition to its tetraethylammonium sensitivity, suggests that the channels mediating I(K(Ca)) behave in a BK type manner. I(K(Ca)) activation was extremely fast, reaching a maximum within 5 ms, and the inactivation was incomplete, stabilizing at a persistent steady-state. I(K(Ca)) was insensitive to intracellular ethylenebis(oxonitrilo)tetraacetate (EGTA), but was abolished by injection of the faster Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), suggesting that voltage-dependent Ca2+ channels and those mediating I(K(Ca)) should be clustered closely on the membrane. Under two-electrode current-clamp recording mode, low amplitude, graded responses were evoked under control conditions, whereas repetitive all-or-none spikes were elicited by application of CTX or after loading the cells with BAPTA. We conclude that I(K(Ca)) activates extremely quickly is persistent and is responsible for the generation and control of the low amplitude, graded, active responses of opener muscle fibres.Peer Reviewe

BDNF is required for the induction of a presynaptic component of the functional conversion of silent synapses

Long-term potentiation (LTP) has received attention because of its proposed role in learning and memory. Despite substantial effort the pre- or postsynaptic expression site of LTP remains unsettled. It has been proposed that LTP is expressed postsynaptically through the functional conversion of >silent synapses.> We had shown that Schaffer collateral (SC) silent and >functional synapses,> which lack and express AMPA receptors, respectively exhibit distinct transmitter release properties. Therefore the functional conversion of silent synapses with LTP should be associated with presynaptic modifications. We now show that the pairing-induced LTP at SC synapses is mediated by combined pre- and postsynaptic modifications involving the postsynaptic emergence of an AMPA response coupled with an enhanced glutamate release. BDNF replicates the changes associated with this LTP by activating TrkBRs, suggesting that the neurotrophin is required for the coordinated changes on both sides of the synaptic cleft. © 2010 Wiley-Liss, Inc.Peer Reviewe

Fast BK-type channel mediates the Ca2+-activated K+ current in crayfish muscle

The role of the Ca2+-activated K+ current (I(K(Ca))) in crayfish opener muscle fibers is functionally important because it regulates the graded electrical activity that is characteristic of these fibers. Using the cell-attached and inside-out configurations of the patch-clamp technique, we found three different classes of channels with properties that matched those expected of the three different ionic channels mediating the depolarization- activated macroscopic currents previously described (Ca2+, K+, and Ca2+dependent K+ currents). We investigated the properties of the ionic channels mediating the extremely fast activating and persistent (I(K(Ca)). These voltage- and Ca2+-activated channels had a mean single-channel conductance of ~ 70 pS and showed a very fast activation. Both the single- channel open probability and the speed of activation increased with depolarization. Both parameters also increased in inside-out patches, i.e., in high Ca2+ concentration. Intracellular loading with the Ca2+ chelator bis(2-aminophenoxy) ethane-N, N,N',N'-tetraacetic acid gradually reduced and eventually prevented channel openings. The channels opened at very brief delays after the pulse depolarization onset (<5 ms), and the time-dependent open probability was constant during sustained depolarization (≤560 ms), matching both the extremely fast activation kinetics and the persistent nature of the macroscopic (I(K(Ca)). However, the intrinsic properties of these single channels do not account for the partial apparent inactivation of the macroscopic (I(K(Ca)), which probably reflects temporal Ca2+ variations in the whole muscle fiber. We conclude that the channels mediating (I(K(Ca)) in crayfish muscle are voltage- and Ca2+-gated BK channels with relatively small conductance. The intrinsic properties of these channels allow them to act as precise Ca2+ sensors that supply the exact feedback current needed to control the graded electrical activity and therefore the contraction of opener muscle fibers.Peer Reviewe