Short-term synaptic plasticity in the rat geniculo-cortical pathway during development in vivo

AbstractInformation transmission in neural networks is influenced by both short-term synaptic plasticity (STP) as well as non-synaptic factors, such as after-hyperpolarization currents and changes in excitability. Although these effects have been widely characterized in vitro using intracellular recordings, how they interact in vivo is unclear. Here we develop a statistical model of the short-term dynamics of spike transmission that aims to disentangle the contributions of synaptic and non-synaptic effects based only on observed pre- and postsynaptic spiking. The model includes a dynamic functional connection with short-term plasticity as well as effects due to the recent history of postsynaptic spiking and slow changes in postsynaptic excitability. Using paired spike recordings, we find that the model accurately describes the short-term dynamics of in vivo spike transmission at a diverse set of identified and putative excitatory synapses, including a thalamothalamic connection in mouse, a thalamocortical connection in a female rabbit, and an auditory brainstem synapse in a female gerbil. We illustrate the utility of this modeling approach by showing how the spike transmission patterns captured by the model may be sufficient to account for stimulus-dependent differences in spike transmission in the auditory brainstem (endbulb of Held). Finally, we apply this model to large-scale multi-electrode recordings to illustrate how such an approach has the potential to reveal cell-type specific differences in spike transmission in vivo. Although short-term synaptic plasticity parameters estimated from ongoing pre- and postsynaptic spiking are highly uncertain, our results are partially consistent with previous intracellular observations in these synapses.Significance StatementAlthough synaptic dynamics have been extensively studied and modeled using intracellular recordings of post-synaptic currents and potentials, inferring synaptic effects from extracellular spiking is challenging. Whether or not a synaptic current contributes to postsynaptic spiking depends not only on the amplitude of the current, but also on many other factors, including the activity of other, typically unobserved, synapses, the overall excitability of the postsynaptic neuron, and how recently the postsynaptic neuron has spiked. Here we developed a model that, using only observations of pre- and postsynaptic spiking, aims to describe the dynamics of in vivo spike transmission by modeling both short-term synaptic plasticity and non-synaptic effects. This approach may provide a novel description of fast, structured changes in spike transmission.

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A Role for Short-Term Synaptic Facilitation and Depression in the Processing of Intensity Information in the Auditory Brain Stem

Journal of Neurophysiology ◽

10.1152/jn.01030.2006 ◽

2007 ◽

Vol 97 (4) ◽

pp. 2863-2874 ◽

Cited By ~ 37

Author(s):

K. M. MacLeod ◽

T. K. Horiuchi ◽

C. E. Carr

Keyword(s):

Synaptic Plasticity ◽

Brain Stem ◽

Time Constant ◽

Cochlear Nucleus ◽

Auditory Nerve ◽

Brain Slices ◽

Fast Time ◽

Short Term ◽

Intensity Information

The nature of the synaptic connection from the auditory nerve onto the cochlear nucleus neurons has a profound impact on how sound information is transmitted. Short-term synaptic plasticity, by dynamically modulating synaptic strength, filters information contained in the firing patterns. In the sound-localization circuits of the brain stem, the synapses of the timing pathway are characterized by strong short-term depression. We investigated the short-term synaptic plasticity of the inputs to the bird's cochlear nucleus angularis (NA), which encodes intensity information, by using chick embryonic brain slices and trains of electrical stimulation. These excitatory inputs expressed a mixture of short-term facilitation and depression, unlike those in the timing nuclei that only depressed. Facilitation and depression at NA synapses were balanced such that postsynaptic response amplitude was often maintained throughout the train at high firing rates (>100 Hz). The steady-state input rate relationship of the balanced synapses linearly conveyed rate information and therefore transmits intensity information encoded as a rate code in the nerve. A quantitative model of synaptic transmission could account for the plasticity by including facilitation of release (with a time constant of ∼40 ms), and a two-step recovery from depression (with one slow time constant of ∼8 s, and one fast time constant of ∼20 ms). A simulation using the model fit to NA synapses and auditory nerve spike trains from recordings in vivo confirmed that these synapses can convey intensity information contained in natural train inputs.

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Unsupervised Formation of Vocalization-Sensitive Neurons: A Cortical Model Based on Short-Term and Homeostatic Plasticity

Neural Computation ◽

10.1162/neco_a_00345 ◽

2012 ◽

Vol 24 (10) ◽

pp. 2579-2603 ◽

Cited By ~ 12

Author(s):

Tyler P. Lee ◽

Dean V. Buonomano

Keyword(s):

Synaptic Plasticity ◽

Direction Selectivity ◽

Homeostatic Plasticity ◽

Cortical Model ◽

Short Term ◽

Temporal Asymmetry ◽

Complex Stimuli ◽

Spike Patterns

The discrimination of complex auditory stimuli relies on the spatiotemporal structure of spike patterns arriving in the cortex. While recordings from auditory areas reveal that many neurons are highly selective to specific spatiotemporal stimuli, the mechanisms underlying this selectivity are unknown. Using computer simulations, we show that selectivity can emerge in neurons in an entirely unsupervised manner. The model is based on recurrently connected spiking neurons and synapses that exhibit short-term synaptic plasticity. During a developmental stage, spoken digits were presented to the network; the only type of long-term plasticity present was a form of homeostatic synaptic plasticity. From an initially unresponsive state, training generated a high percentage of neurons that responded selectively to individual digits. Furthermore, units within the network exhibited a cardinal feature of vocalization-sensitive neurons in vivo: differential responses between forward and reverse stimulus presentations. Direction selectivity deteriorated significantly, however, if short-term synaptic plasticity was removed. These results establish that a simple form of homeostatic plasticity is capable of guiding recurrent networks into regimes in which complex stimuli can be discriminated. In addition, one computational function of short-term synaptic plasticity may be to provide an inherent temporal asymmetry, thus contributing to the characteristic forward-reverse selectivity.

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Low level postnatal methylmercury exposure in vivo alters developmental forms of short-term synaptic plasticity in the visual cortex of rat

Toxicology and Applied Pharmacology ◽

10.1016/j.taap.2009.07.037 ◽

2009 ◽

Vol 240 (3) ◽

pp. 412-422 ◽

Cited By ~ 11

Author(s):

Sameera Dasari ◽

Yukun Yuan

Keyword(s):

Synaptic Plasticity ◽

Visual Cortex ◽

Short Term ◽

Low Level ◽

Methylmercury Exposure ◽

Exposure In Vivo

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Altered short-term synaptic plasticity and reduced muscle strength in mice with impaired regulation of presynaptic CaV2.1 Ca2+ channels

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1524650113 ◽

2016 ◽

Vol 113 (4) ◽

pp. 1068-1073 ◽

Cited By ~ 7

Author(s):

Evanthia Nanou ◽

Jin Yan ◽

Nicholas P. Whitehead ◽

Min Jeong Kim ◽

Stanley C. Froehner ◽

...

Keyword(s):

Synaptic Plasticity ◽

Muscle Strength ◽

Neuromuscular Junction ◽

Synaptic Transmission ◽

Motor Coordination ◽

Tibialis Anterior Muscle ◽

Short Term ◽

Synaptic Facilitation ◽

Cas Proteins

Facilitation and inactivation of P/Q-type calcium (Ca2+) currents through the regulation of voltage-gated Ca2+ (CaV) 2.1 channels by Ca2+ sensor (CaS) proteins contributes to the facilitation and rapid depression of synaptic transmission in cultured neurons that transiently express CaV2.1 channels. To examine the modulation of endogenous CaV2.1 channels by CaS proteins in native synapses, we introduced a mutation (IM-AA) into the CaS protein-binding site in the C-terminal domain of CaV2.1 channels in mice, and tested synaptic facilitation and depression in neuromuscular junction synapses that use exclusively CaV2.1 channels for Ca2+ entry that triggers synaptic transmission. Even though basal synaptic transmission was unaltered in the neuromuscular synapses in IM-AA mice, we found reduced short-term facilitation in response to paired stimuli at short interstimulus intervals in IM-AA synapses. In response to trains of action potentials, we found increased facilitation at lower frequencies (10–30 Hz) in IM-AA synapses accompanied by slowed synaptic depression, whereas synaptic facilitation was reduced at high stimulus frequencies (50–100 Hz) that would induce strong muscle contraction. As a consequence of altered regulation of CaV2.1 channels, the hindlimb tibialis anterior muscle in IM-AA mice exhibited reduced peak force in response to 50 Hz stimulation and increased muscle fatigue. The IM-AA mice also had impaired motor control, exercise capacity, and grip strength. Taken together, our results indicate that regulation of CaV2.1 channels by CaS proteins is essential for normal synaptic plasticity at the neuromuscular junction and for muscle strength, endurance, and motor coordination in mice in vivo.

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Altered synaptic plasticity and central pattern generator dysfunction in a Drosophila model of PNKD3 paroxysmal dyskinesia

10.1101/2020.02.20.957639 ◽

2020 ◽

Author(s):

Simon Lowe ◽

Patrick Kratschmer ◽

James E.C. Jepson

Keyword(s):

Synaptic Plasticity ◽

Central Pattern Generator ◽

Neurotransmitter Release ◽

Ex Vivo ◽

Pattern Generator ◽

Bk Channels ◽

Video Tracking ◽

Bk Channel ◽

Short Term

ABSTRACTBackgroundParoxysmal non-kinesigenic dyskinesia type-3 (PNKD3) has been linked to gain-of-function (GOF) mutations in the hSlo1 BK potassium channel, in particular a dominant mutation (D434G) that enhances Ca2+-sensitivity. However, while BK channels play well-known roles in regulating neurotransmitter release, it is unclear whether the D434G mutation alters neurotransmission and synaptic plasticity in vivo. Furthermore, the subtypes of movement-regulating circuits impacted by this mutation are unknown.ObjectivesWe aimed to use a larval Drosophila model of PNKD3 (sloE366G/+) to examine how BK channel GOF in dyskinesia alters synaptic properties and motor circuit function.MethodsWe used video-tracking to test for movement defects in sloE366G/+ larvae, and sharp-electrode recordings to assess the fidelity of Ca2+-dependent neurotransmitter release and short-term plasticity at the neuromuscular junction. We then combined sharp-electrode recording with ex vivo Ca2+-imaging to investigate the functionality of the central pattern generator (CPG) driving foraging behavior in sloE366G/+ larvae.ResultsWe show that the PNKD3 mutation leads to Ca2+-dependent alterations in synaptic release and paired-pulse facilitation. Furthermore, we identify robust alterations in locomotor behaviors in sloE366G/+ larvae which were mirrored by dysfunction of the upstream, movement-generating CPG in the larval ventral nerve cord.ConclusionOur results demonstrate that a BK channel GOF mutation can alter neurotransmitter release and short-term synaptic plasticity, and result in CPG dysfunction, in Drosophila larvae. These data add to a growing body of work linking paroxysmal dyskinesias to aberrant neuronal excitability and synaptic plasticity in pre-motor circuits.

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Leucine Carboxyl Methyltransferase 1 Overexpression Protects Against Cognitive and Electrophysiological Impairments in Tg2576 APP Transgenic Mice

Journal of Alzheimer s Disease ◽

10.3233/jad-200462 ◽

2021 ◽

Vol 79 (4) ◽

pp. 1813-1829

Author(s):

Madhumathi Gnanaprakash ◽

Agnieszka Staniszewski ◽

Hong Zhang ◽

Rose Pitstick ◽

Michael P. Kavanaugh ◽

...

Keyword(s):

Synaptic Plasticity ◽

Transgenic Mice ◽

Protein Phosphatase ◽

Cognitive Impairments ◽

Amyloid Β ◽

Molecular Pathogenesis ◽

Short Term ◽

Tg2576 Mice ◽

Pathogenic Effects

Background: The serine/threonine protein phosphatase, PP2A, is thought to play a central role in the molecular pathogenesis of Alzheimer’s disease (AD), and the activity and substrate specificity of PP2A is regulated, in part, through methylation and demethylation of its catalytic subunit. Previously, we found that transgenic overexpression of the PP2A methyltransferase, LCMT-1, or the PP2A methylesterase, PME-1, altered the sensitivity of mice to impairments caused by acute exposure to synthetic oligomeric amyloid-β (Aβ). Objective: Here we sought to test the possibility that these molecules also controlled sensitivity to impairments caused by chronically elevated levels of Aβ produced in vivo. Methods: To do this, we examined the effects of transgenic LCMT-1, or PME-1 overexpression on cognitive and electrophysiological impairments caused by chronic overexpression of mutant human APP in Tg2576 mice. Results: We found that LCMT-1 overexpression prevented impairments in short-term spatial memory and synaptic plasticity in Tg2576 mice, without altering APP expression or soluble Aβ levels. While the magnitude of the effects of PME-1 overexpression in Tg2576 mice was small and potentially confounded by the emergence of non-cognitive impairments, Tg2576 mice that overexpressed PME-1 showed a trend toward earlier onset and/or increased severity of cognitive and electrophysiological impairments. Conclusion: These data suggest that the PP2A methyltransferase, LCMT-1, and the PP2A methylesterase, PME-1, may participate in the molecular pathogenesis of AD by regulating sensitivity to the pathogenic effects of chronically elevated levels of Aβ.

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