[Show abstract][Hide abstract]ABSTRACT: The feedforward dentate gyrus-CA3 microcircuit in the hippocampus is thought to activate ensembles of CA3 pyramidal cells and interneurons to encode and retrieve episodic memories. The creation of these CA3 ensembles depends on neuromodulatory input and synaptic plasticity within this microcircuit. Here we review the mechanisms by which the neuromodulators aceylcholine, noradrenaline, dopamine, and serotonin reconfigure this microcircuit and thereby infer the net effect of these modulators on the processes of episodic memory encoding and retrieval.
Full-text available · Article · Oct 2016 · Frontiers in Synaptic Neuroscience
[Show abstract][Hide abstract]ABSTRACT: Selective blockade of inhibitory synaptic transmission onto specific neurons is a useful tool for dissecting the excitatory and inhibitory synaptic components of ongoing network activity. To achieve this, intracellular recording with a patch solution capable of blocking GABAA receptors has advantages over other manipulations, such as pharmacological application of GABAergic antagonists or optogenetic inhibition of populations of interneurones, in that the majority of inhibitory transmission is unaffected and hence the remaining network activity preserved. Here, we assess three previously described methods to block inhibition: intracellular application of the molecules picrotoxin, 4,4’-dinitro-stilbene-2,2’-disulphonic acid (DNDS) and 4,4’-diisothiocyanostilbene-2,2’-disulphonic acid (DIDS). DNDS and picrotoxin were both found to be ineffective at blocking evoked, monosynaptic inhibitory postsynaptic currents (IPSCs) onto mouse CA1 pyramidal cells. An intracellular solution containing DIDS and caesium fluoride, but lacking nucleotides ATP and GTP, was effective at decreasing the amplitude of IPSCs. However, this effect was found to be independent of DIDS, and the absence of intracellular nucleotides, and was instead due to the presence of fluoride ions in this intracellular solution, which also blocked spontaneously occurring IPSCs during hippocampal sharp waves. Critically, intracellular fluoride ions also caused a decrease in both spontaneous and evoked excitatory synaptic currents and precluded the inclusion of nucleotides in the intracellular solution. Therefore, of the methods tested, only fluoride ions were effective for intracellular blockade of IPSCs but this approach has additional cellular effects reducing its selectivity and utility.
Full-text available · Article · Aug 2016 · PLoS ONE
[Show abstract][Hide abstract]ABSTRACT: NMR spectra of DNDS (purchased from Fluorochem Ltd.).
A) and B) show spectra consistent with the structure of DNDS. A) 1H NMR taken on a Varian 400 MR spectrometer in D20 with insert showing close-up of relevant peaks. B) 13C NMR taken on a Varian 400 MR spectrometer in D20 with insert of compound structure.
[Show abstract][Hide abstract]ABSTRACT: [CaCaM] transients elicited by classical LTP-inducing STDP protocols are sensitive to SK-blockade whereas other compound and unitary stimuli are not.
EPSPs were required for SK-channel activation since SK-channel cluster was spatially coupled to NMDAR cluster (50nm) for these simulations. Bar charts in end column summarize global and nanodomain peak [CaCaM].
[Show abstract][Hide abstract]ABSTRACT: Reaction network of Ca2+ /calmodulin co-operative binding.
Nx and Cx, represent calmodulin N- and C-lobe Ca2+ binding-sites. Binding sites are initially in state T, with associated binding rates kon(T)x and koff(T)x. Upon binding Ca2+, the lobe’s remaining Ca2+ binding site instantaneously switches to R state, with associated binding rates kon(R)x and koff(R)x.
[Show abstract][Hide abstract]ABSTRACT: (A) Concentration gradients of peak activated [CaCaM] in NMDA and VGCC nanodomains during EPSP-bAP induction protocols. Each curve represents different simulated values for CaM diffusivity. (B) Activated [CaCaM] is increased by SK-blockade across CaM diffusivities. Very immobile CaM results in heightened effect of SK-blockade on activated [CaCaM] (see also C). (C) Ratio of peak [CaCaM] for SK-channel conditions. Subscript 0 indicates that SK-channels were blocked and subscript 1 indicates SK-channels were active.
[Show abstract][Hide abstract]ABSTRACT: Low-pass filtering of global [Ca2+] signals by endogenous Ca2+ buffers.
Additional stimuli for Fig 2. Nanodomain [Ca2+] is defined as Ca2+ concentration at 50nm radial distance from channel cluster.
[Show abstract][Hide abstract]ABSTRACT: The key trigger for Hebbian synaptic plasticity is influx of Ca2+ into postsynaptic dendritic spines. The magnitude of [Ca2+] increase caused by NMDA-receptor (NMDAR) and voltage-gated Ca2+ -channel (VGCC) activation is thought to determine both the amplitude and direction of synaptic plasticity by differential activation of Ca2+ -sensitive enzymes such as calmodulin. Ca2+ influx is negatively regulated by Ca2+ -activated K+ channels (SK-channels) which are in turn inhibited by neuromodulators such as acetylcholine. However, the precise mechanisms by which SK-channels control the induction of synaptic plasticity remain unclear. Using a 3-dimensional model of Ca2+ and calmodulin dynamics within an idealised, but biophysically-plausible, dendritic spine, we show that SK-channels regulate calmodulin activation specifically during neuron-firing patterns associated with induction of spike timing-dependent plasticity. SK-channel activation and the subsequent reduction in Ca2+ influx through NMDARs and L-type VGCCs results in an order of magnitude decrease in calmodulin (CaM) activation, providing a mechanism for the effective gating of synaptic plasticity induction. This provides a common mechanism for the regulation of synaptic plasticity by neuromodulators.
Full-text available · Article · May 2016 · PLoS Computational Biology
[Show abstract][Hide abstract]ABSTRACT: (A) Concentration gradients of peak activated [CaCaM] in NMDA and VGCC nanodomains during EPSP-bAP induction protocols. Each curve represents different simulated values for L-type channel cluster conductance. (B) Activated [CaCaM] is increased by SK-blockade across a range of L-type conductances although differences are enhanced as L-type conductance is increased (see also C). (C) Ratio of peak [CaCaM] for SK-channel conditions blocked or coupled to NMDARs. Subscript 0 indicates that SK-channels were blocked and subscript 1 indicates SK-channels were active.
[Show abstract][Hide abstract]ABSTRACT: Ca2+ buffer parameter sweeps.
Comparison of global and nanodomain [Ca2+] transients for EPSP+bAP stimulation protocol. Nanodomain [Ca2+] is defined as [Ca2+] at 20nm radial distance from channel cluster. Simulations use the simple binding scheme for Ca2+ to mobile Ca2+ buffer described in equation system 17. The first two columns show transients for simulations where EFB parameters were fixed and the concentration of the mobile buffer was varied. Mobile Ca2+ buffer parameter values were selected to represent a typical ‘fast’ mobile buffer and a ‘slow’ mobile buffer. Slow mobile buffer binding parameters were set to match estimates for calbindin  and fast mobile buffer was set to CaM N-lobe binding rates . The end two columns show transients for simulations where the mobile Ca2+ buffer was set to 100μM calbindin and either the EFB binding forward rate or EFB affinity was fixed while the other varied.
[Show abstract][Hide abstract]ABSTRACT: (A) Peak [Ca2+] gradients in Ca2+ channel nanodomains across buffer condition and spine stimuli. (B) Peak [Ca2+] gradients in Ca2+ channel nanodomains in the presence of EFB and 100μM calbindin. Each curve represents a different stimulation pattern. Dashed horizontal lines in all plots indicate SK half-activation parameter, Ks = 0.33μM.
[Show abstract][Hide abstract]ABSTRACT: Global and nanodomain (20nm from channel cluster) time courses of [Ca2+] and CaCaM species concentrations across different spine stimuli.
SK-channels were active and spatially coupled (50nm) to NMDAR cluster.
[Show abstract][Hide abstract]ABSTRACT: The effect of SK-blockade on [CaCaM] transients elicited by EPSP-bAP protocol for two VGCC spatial arrangements.
Clustered VGCC condition refers to the VGCC arrangement described in the main text and illustrated in Fig 1. Uniform VGCC condition refers to the case where the total VGCC conductance is spread uniformly across the entire surface of the spine. VGCC nanodomain, for both spatial arrangements of VGCCs, is defined as a point 20nm radial distance from the VGCC Ca2+—source in the clustered case.
[Show abstract][Hide abstract]ABSTRACT: Place cell firing patterns reactivated during hippocampal sharp-wave ripples (SWRs) in rest or sleep are thought to induce synaptic plasticity and thereby promote the consolidation of recently encoded information. However, the capacity of reactivated spike trains to induce plasticity has not been directly tested. Here, we show that reactivated place cell firing patterns simultaneously recorded from CA3 and CA1 of rat dorsal hippocampus are able to induce long-term potentiation (LTP) at synapses between CA3 and CA1 cells but only if accompanied by SWR-associated synaptic activity and resulting dendritic depolarization. In addition, we show that the precise timing of coincident CA3 and CA1 place cell spikes in relation to SWR onset is critical for the induction of LTP and predictive of plasticity generated by reactivation. Our findings confirm an important role for SWRs in triggering and tuning plasticity processes that underlie memory consolidation in the hippocampus during rest or sleep.
Full-text available · Article · Feb 2016 · Cell Reports