Disinhibition-mediated LTP in the hippocampus is synapse specific (original) (raw)
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The Journal of Neuroscience, 2020
Synaptic plasticity is triggered by different patterns of network activity. Here, we investigated how LTP in CA3-CA1 synapses induced by different stimulation patterns is affected by tonic GABA A conductances in rat hippocampal slices. Spike-timingdependent LTP was induced by pairing Schaffer collateral stimulation with antidromic stimulation of CA1 pyramidal neurons. Theta-burst-induced LTP was induced by theta-burst stimulation of Schaffer collaterals. We mimicked increased tonic GABA A conductance by bath application of 30 lM GABA. Surprisingly, tonic GABA A conductance selectively suppressed theta-burstinduced LTP but not spike-timing-dependent LTP. We combined whole-cell patch-clamp electrophysiology, two-photon Ca 21 imaging, glutamate uncaging, and mathematical modeling to dissect the mechanisms underlying these differential effects of tonic GABA A conductance. We found that Ca 21 transients during pairing of an action potential with an EPSP were less sensitive to tonic GABA A conductance-induced shunting inhibition than Ca 21 transients induced by EPSP burst. Our results may explain how different forms of memory are affected by increasing tonic GABA A conductances under physiological or pathologic conditions, as well as under the influence of substances that target extrasynaptic GABA A receptors (e.g., neurosteroids, sedatives, antiepileptic drugs, and alcohol).
Disinhibition mediates a form of hippocampal long-term potentiation in area CA1
PloS one, 2009
The hippocampus plays a central role in memory formation in the mammalian brain. Its ability to encode information is thought to depend on the plasticity of synaptic connections between neurons. In the pyramidal neurons constituting the primary hippocampal output to the cortex, located in area CA1, firing of presynaptic CA3 pyramidal neurons produces monosynaptic excitatory postsynaptic potentials (EPSPs) followed rapidly by feedforward (disynaptic) inhibitory postsynaptic potentials (IPSPs). Long-term potentiation (LTP) of the monosynaptic glutamatergic inputs has become the leading model of synaptic plasticity, in part due to its dependence on NMDA receptors (NMDARs), required for spatial and temporal learning in intact animals. Using whole-cell recording in hippocampal slices from adult rats, we find that the efficacy of synaptic transmission from CA3 to CA1 can be enhanced without the induction of classic LTP at the glutamatergic inputs. Taking care not to directly stimulate inhibitory fibers, we show that the induction of GABAergic plasticity at feedforward inhibitory inputs results in the reduced shunting of excitatory currents, producing a long-term increase in the amplitude of Schaffer collateral-mediated postsynaptic potentials. Like classic LTP, disinhibition-mediated LTP requires NMDAR activation, suggesting a role in types of learning and memory attributed primarily to the former and raising the possibility of a previously unrecognized target for therapeutic intervention in disorders linked to memory deficits, as well as a potentially overlooked site of LTP expression in other areas of the brain.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2000
Activity-dependent synaptic plasticity is critical for learning and memory. Considerable attention has been paid to mechanisms that increase or decrease synaptic efficacy, referred to as long-term potentiation (LTP) and long-term depression (LTD), respectively. It is becoming apparent that synaptic activity also modulates the ability to elicit subsequent synaptic changes. We provide direct experimental evidence that this modulation is attributable, at least in part, to variations in the level of postsynaptic depolarization required for inducing plasticity. In slices from adult hippocampal CA1, a brief pairing protocol known to produce LTP can also induce LTD. The voltage-response function for the induction of LTD and LTP in naive synapses exhibits three parts: at a postsynaptic membrane potential during pairing (V(m)) </= -40 mV, no synaptic modification is obtained; at V(m) between -40 and -20 mV, LTD is induced; and, finally, at V(m) > -20 mV, LTP is generated. This function...
2010
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Inhibitory synaptic plasticity regulates pyramidal neuron spiking in the rodent hippocampus
2008
Spike-timing modifies the efficacy of both excitatory and inhibitory synapses onto CA1 pyramidal neurons in the rodent hippocampus. Repetitively spiking the presynaptic neuron before the postsynaptic neuron induces inhibitory synaptic plasticity, which results in a depolarization of the reversal potential for GABA (E GABA ). Our goal was to determine how inhibitory synaptic plasticity regulates CA1 pyramidal neuron spiking in the rat hippocampus. We demonstrate electrophysiologically that depolarizing E GABA by 24.7 mV increased the spontaneous action potential firing frequency of cultured hippocampal neurons 254% from 0.12؎0.07 Hz to 0.44؎0.13 Hz (n;11؍ P<0.05). Next we used a single compartment model of a CA1 pyramidal neuron to explore in detail how inhibitory synaptic plasticity of feedforward and feedback inhibition regulates the generation of action potentials, spike latency, and the minimum excitatory conductance required to generate an action potential; plasticity was modeled as a depolarization of E GABA , which effectively weakens inhibition. Depolarization of E GABA at feedforward and feedback inhibitory synapses decreased the latency to the 1st spike by 2.27 ms, which was greater that the sum of the decreases produced by depolarizing E GABA at feedforward (0.85 ms) or feedback inhibitory synapses (0.02 ms) alone. In response to a train of synaptic inputs, depolarizing E GABA decreased the inter-spike interval and increased the number of output spikes in a frequency dependent manner, improving the reliability of input-output transmission. Moreover, a depolarizing shift in E GABA at feedforward and feedback synapses triggered by spike trains recorded from CA1 pyramidal layer neurons during field theta from anesthetized rats, significantly increased spiking on the up-and down-strokes of the first half of the theta rhythm (P<0.05), without changing the preferred phase of firing (P.)387.0؍ This study provides the first explanation of how depolarizing E GABA affects pyramidal cell output within the hippocampus. (M. A. Woodin).
GABAergic synaptic transmission regulates calcium influx during spike-timing dependent plasticity
Frontiers in Synaptic Neuroscience, 2010
Early in development, coincident pre-and postsynaptic activity strengthens inhibition through a Ca 2+ -dependent regulation of NKCC1, which hyperpolarizes E Cl . The same pattern of neuronal activity also modifies GABAergic transmission in the mature nervous system through a Ca 2+ -dependent decrease in KCC2 activity, which depolarizes E Cl . The spike-timing window for mature GABAergic inhibition has been characterized as symmetrical. Both positive and negative spike-timing intervals (within 15 ms; ±15 ms) decrease the strength of inhibition due to E Cl depolarization (as described above). Noncoincident activity (±50 ms) also reduces inhibition, but through a decrease in conductance .
Proceedings of the National Academy of Sciences, 2004
Spontaneously occurring neuronal oscillations constitute a hallmark of developmental networks. They have been observed in the retina, neocortex, hippocampus, thalamus, and spinal cord. In the immature hippocampus, the so-called “giant depolarizing potentials” (GDPs) are network-driven synaptic events generated by γ-aminobutyric acid (GABA), which at this stage is depolarizing and excitatory. We have tested the hypothesis that during the first postnatal week, GDP-associated calcium signals may alter the properties of synaptic transmission at poorly developed mossy fiber (MF)-CA3 connections. We found that “pairing” GDPs with MF stimulation induced a persistent increase in synaptic efficacy at MF-CA3 synapses. When the interval between GDPs and MF stimulation was increased, the potentiating effect progressively declined and disappeared. The potentiation depended on activation of voltage-dependent calcium channels and calcium flux. This activity may contribute to the refinement of neur...
Tonic GABAA conductance favors temporal over rate coding in the rat hippocampus
Synaptic plasticity is triggered by different patterns of neuronal network activity. Network activity leads to an increase in ambient GABA concentration and tonic activation of GABAA receptors. How tonic GABAA conductance affects synaptic plasticity during temporal and rate-based coding is poorly understood. Here, we show that tonic GABAA conductance differently affects long-term potentiation (LTP) induced by different stimulation patterns. The LTP based on a temporal spike - EPSP order (spike-timing-dependent [st] LTP) was not affected by exogenous GABA application. Backpropagating action potential, which enables Ca2+ entry through N-methyl-D-aspartate receptors (NMDARs) during stLTP induction, was only slightly reduced by the tonic conductance. In contrast, GABA application impeded LTP dependent on spiking rate (theta-burst-induced [tb] LTP) by reducing the EPSP bust response and, hence, NMDAR-mediated Ca2+ entry during tbLTP induction. Our results may explain the changes in diffe...
The Depolarizing Action of GABA Controls Early Network Activity in the Developing Hippocampus
Molecular Neurobiology, 2010
Early in postnatal life γ-aminobutyric acid (GABA), the primary inhibitory transmitter in adults, excites targeted neurons by an outwardly directed flux of chloride which results from the unbalance between the cation-chloride cotransporters NKCC1 and KCC2, involved in chloride uptake and extrusion, respectively. This effect contributes to generate synchronized network activity or giant depolarizing potentials (GDPs) in the developing hippocampus. Here, we review some recent data concerning the mechanisms by which GDPs are generated and their functional role in enhancing synaptic efficacy at poorly developed GABAergic and glutamatergic synapses. In adulthood, reshaping neuronal circuits due to changes in chloride homeostasis and to the shift of GABA from hyperpolarizing to depolarizing, has been implicated in several neurological disorders, including epilepsy. Evidence has been recently provided that in chronically nerve growth factor-deprived mice expressing a progressive agedependent neurodegenerative pathology resembling that observed in patients with Alzheimer's disease, the reduced expression of mRNA encoding for the Kcc2 gene and the depolarizing action of GABA lead to the reorganization of the neuronal hippocampal network. This may represent a novel mechanism by which GABAergic signaling counterbalances the loss of synaptic activity in neurodegenerative diseases.
Disinhibitory and neuromodulatory regulation of hippocampal synaptic plasticity
2020
Hippocampal synaptic plasticity, particularly in the Schaffer collateral (SC) to CA1 pyramidal excitatory transmission, is considered as the cellular mechanism underlying learning. The CA1 pyramidal neurons are embedded in an intricate local circuitry that contains a variety of interneurons. The roles these interneurons play in the regulation of the excitatory synaptic plasticity remains largely understudied. Our recent experiments showed that repeated cholinergic activation of α7 nACh receptors expressed in oriens-lacunosum-moleculare (OLMα2) interneurons could induce LTP in SC-CA1 synapses, likely through disinhibition by inhibiting stratum radiatum (s.r.) interneurons that provide feedforward inhibition onto CA1 pyramidal neurons, revealing a potential mechanism for local interneurons to regulate SC-CA1 synaptic plasticity. Here, we pair in vitro studies with biophysically-based modeling to uncover the mechanisms through which cholinergic-activated GABAergic interneurons can disi...