Synaptic Plasticity Depends on the Fine-Scale Input Pattern in Thin Dendrites of CA1 Pyramidal Neurons

Synaptic plasticity rules change during development: while hippocampal synapses can be potentiated by a single action potential pairing protocol in young neurons, mature neurons require burst firing to induce synaptic potentiation. An essential component for spike timing-dependent plasticity is the backpropagating action potential (BAP). BAP along the dendrites can be modulated by morphology and ion channel composition, both of which change during late postnatal development. However, it is unclear whether these dendritic changes can explain the developmental changes in synaptic plasticity induction rules. Here, we show that tonic GABAergic inhibition regulates dendritic action potential backpropagation in adolescent, but not preadolescent, CA1 pyramidal neurons. These developmental changes in tonic inhibition also altered the induction threshold for spike timing-dependent plasticity in adolescent neurons. This GABAergic regulatory effect on backpropagation is restricted to distal regions of apical dendrites (>200 μm) and mediated by α5-containing GABA(A) receptors. Direct dendritic recordings demonstrate α5-mediated tonic GABA(A) currents in adolescent neurons which can modulate BAPs. These developmental modulations in dendritic excitability could not be explained by concurrent changes in dendritic morphology. To explain our data, model simulations propose a distally increasing or localized distal expression of dendritic α5 tonic inhibition in mature neurons. Overall, our results demonstrate that dendritic integration and plasticity in more mature dendrites are significantly altered by tonic α5 inhibition in a dendritic region-specific and developmentally regulated manner.

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Disinhibitory and neuromodulatory regulation of hippocampal synaptic plasticity

10.1101/2020.10.13.337188 ◽

2020 ◽

Author(s):

Inês Guerreiro ◽

Zhenglin Gu ◽

Jerrel L. Yakel ◽

Boris S. Gutkin

Keyword(s):

Synaptic Plasticity ◽

Pyramidal Neurons ◽

Pyramidal Cells ◽

General Mechanism ◽

Excitatory Synapses ◽

Ca1 Pyramidal Cells ◽

Ca1 Pyramidal Neurons ◽

Hippocampal Synaptic Plasticity ◽

Local Circuitry ◽

Feedforward Inhibition

AbstractHippocampal 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 disinhibit CA1 pyramidal cells, and how repeated disinhibition modulates hippocampal plasticity at the excitatory synapses. We found that α7 nAChR activation increases OLM activity. OLM neurons, in turn inhibit the fast-spiking interneurons that provide feedforward inhibition onto CA1 pyramidal neurons. This disinhibition, paired with tightly timed SC stimulation, can induce potentiation at the excitatory synapses of CA1 pyramidal neurons. Our work further describes the pairing of disinhibition with SC stimulation as a general mechanism for the induction of hippocampal synaptic plasticity.Disinhibition of the excitatory synapses, paired with SC stimulation, leads to increased NMDAR activation and intracellular calcium concentration sufficient to upregulate AMPAR permeability and potentiate the synapse. Repeated paired disinhibition of the excitatory synapse leads to larger and longer lasting increases of the AMPAR permeability. Our study thus provides a novel mechanism for inhibitory interneurons to directly modify glutamatergic synaptic plasticity. In particular, we show how cholinergic action on OLM interneurons can down-regulate the GABAergic signaling onto CA1 pyramidal cells, and how this shapes local plasticity rules. We identify paired disinhibition with SC stimulation as a general mechanism for the induction of hippocampal synaptic plasticity.

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Bidirectional Synaptic Plasticity Is Driven by Sex Neurosteroids Targeting Estrogen and Androgen Receptors in Hippocampal CA1 Pyramidal Neurons

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2019.00534 ◽

2019 ◽

Vol 13 ◽

Cited By ~ 2

Author(s):

Alessandro Tozzi ◽

Valentina Durante ◽

Paolo Manca ◽

Michela Di Mauro ◽

Juan Blasi ◽

...

Keyword(s):

Synaptic Plasticity ◽

Pyramidal Neurons ◽

Androgen Receptors ◽

Ca1 Pyramidal Neurons ◽

Hippocampal Ca1

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Attenuation of the extracellular matrix increases the number of synapses but suppresses synaptic plasticity

10.1101/2020.04.23.058115 ◽

2020 ◽

Author(s):

Yulia Dembitskaya ◽

Nikolay Gavrilov ◽

Igor Kraev ◽

Maxim Doronin ◽

Olga Tyurikova ◽

...

Keyword(s):

Extracellular Matrix ◽

Synaptic Plasticity ◽

Dendritic Spines ◽

Pyramidal Neurons ◽

Long Term Potentiation ◽

Excitatory Postsynaptic Potential ◽

Sk Channels ◽

Ca1 Pyramidal Neurons ◽

Section Electron ◽

Serial Section Electron Microscopy

AbstractThe brain extracellular matrix (ECM) is a proteoglycan complex that occupies the extracellular space between brain cells and regulates brain development, brain wiring, and synaptic plasticity. However, the action of the ECM on synaptic plasticity remains controversial. Here, we employed serial section electron microscopy to show that enzymatic attenuation of ECM with chondroitinase ABC (ChABC) triggers the appearance of new glutamatergic synapses onto thin dendritic spines of CA1 pyramidal neurons. The appearance of new synapses increased the ratio of the field excitatory postsynaptic potential (fEPSP) to presynaptic fiber volley (PrV), suggesting that these new synapses are formed on existing axonal fibers. However, both the mean miniature excitatory postsynaptic current (mEPSC) amplitude and AMPA/NMDA ratio were decreased, suggesting that ECM attenuation increased the proportion of ‘unpotentiated’ synapses. A higher proportion of unpotentiated synapses would be expected to promote long-term potentiation (LTP). Surprisingly, theta-burst induced LTP was suppressed by ChABC treatment. The suppression of LTP was accompanied by decreased excitability of CA1 pyramidal neurons due to the upregulation of small conductance Ca2+-activated K+ (SK) channels. A pharmacological blockade of SK channels restored cell excitability and, expectedly, enhanced LTP above the level of control. This enhancement of LTP was abolished by a blockade of Rho-associated protein kinase (ROCK), which is involved in the maturation of dendritic spines. Thus, ECM attenuation enables the appearance of new synapses in the hippocampus, which is compensated for by a reduction in the excitability of postsynaptic neurons, thereby preventing network overexcitation at the expense of synaptic plasticity.

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Microglia mediate synaptic plasticity induced by 10 Hz repetitive magnetic stimulation

10.1101/2021.10.03.462905 ◽

2021 ◽

Author(s):

Amelie Eichler ◽

Dimitrios Kleidonas ◽

Zsolt Turi ◽

Matthias Kirsch ◽

Dietmar Pfeifer ◽

...

Keyword(s):

Synaptic Plasticity ◽

Functional Properties ◽

Magnetic Stimulation ◽

Pyramidal Neurons ◽

Therapeutic Effects ◽

Tissue Cultures ◽

Ca1 Pyramidal Neurons ◽

Structural And Functional Properties ◽

Repetitive Magnetic Stimulation

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that is widely used in clinical practice for therapeutic purposes. Nevertheless, the mechanisms that mediate its therapeutic effects remain poorly understood. Recent work implicates that microglia, the resident immune cells of the central nervous system, have a defined role in the regulation of physiological brain function, e.g. the expression of synaptic plasticity. Despite this observation, no evidence exists for a role of microglia in excitatory synaptic plasticity induced by rTMS. Here, we used repetitive magnetic stimulation of organotypic entorhino-hippocampal tissue cultures to test for the role of microglia in synaptic plasticity induced by 10 Hz repetitive magnetic stimulation (rMS). For this purpose, we performed PLX3397 (Pexidartinib) treatment to deplete microglia from tissue culture preparations. Using whole-cell patch-clamp recordings, live-cell microscopy, immunohistochemistry and transcriptome analysis, we assessed structural and functional properties of both CA1 pyramidal neurons and microglia to correlate the microglia phenotype to synaptic plasticity. PLX3397 treatment over 18 days reliably depletes microglia in tissue cultures, without affecting structural and functional properties of CA1 pyramidal neurons. Microglia-depleted cultures display defects in the ability of CA1 pyramidal neurons to express plasticity of excitatory synapses upon rMS. Notably, rMS induces a moderate release of proinflammatory and plasticity-promoting factors, while microglial morphology stays unaltered. We conclude that microglia play a crucial role in rMS-induced excitatory synaptic plasticity.

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