Learning to Discriminate Through Long-Term Changes of Dynamical Synaptic Transmission

Short-term synaptic plasticity is modulated by long-term synaptic changes. There is, however, no general agreement on the computational role of this interaction. Here, we derive a learning rule for the release probability and the maximal synaptic conductance in a circuit model with combined recurrent and feedforward connections that allows learning to discriminate among natural inputs. Short-term synaptic plasticity thereby provides a nonlinear expansion of the input space of a linear classifier, whereas the random recurrent network serves to decorrelate the expanded input space. Computer simulations reveal that the twofold increase in the number of input dimensions through short-term synaptic plasticity improves the performance of a standard perceptron up to 100%. The distributions of release probabilities and maximal synaptic conductances at the capacity limit strongly depend on the balance between excitation and inhibition. The model also suggests a new computational interpretation of spikes evoked by stimuli outside the classical receptive field. These neuronal activitiesmay reflect decorrelation of the expanded stimulus space by intracortical synaptic connections

Natural Spike Trains Trigger Short- and Long-Lasting Dynamics at Hippocampal Mossy Fiber Synapses in Rodents

Synapses exhibit strikingly different forms of plasticity over a wide range of time scales, from milliseconds to hours. Studies on synaptic plasticity typically use constant-frequency stimulation to activate synapses, whereas in vivo activity of neurons is irregular.Using extracellular and whole-cell electrophysiological recordings, we have here studied the synaptic responses at hippocampal mossy fiber synapses in vitro to stimulus patterns obtained from in vivo recordings of place cell firing of dentate gyrus granule cells in behaving rodents. We find that synaptic strength is strongly modulated on short- and long-lasting time scales during the presentation of the natural stimulus trains.We conclude that dynamic short- and long-term synaptic plasticity at the hippocampal mossy fiber synapse plays a prominent role in normal synaptic function

The hippocampal mossy fiber synapse

Synapsen sind die spezialisierten subzellulären Kontaktstellen im Gehirn, die die Kommunikation zwischen einzelnen Nervenzellen, den Neuronen, auf elektrischem oder chemischem Weg ermöglichen. Anatomisch und physiologisch sind Synapsen jedoch erstaunlich divers, unter anderem abhängig von der untersuchten Hirnregion, der Identität der prä- und postsynaptischen Neurone, den präsynaptisch ausgeschütteten Neurotransmittern und postsynaptischen Rezeptorsystemen. Generell kann die Effektivität oder Stärke synaptischer Übertragung durch unterschiedliche Mechanismen beeinflusst werden. Hier werden nun Mechanismen, Ausprägung und funktionelle Relevanz von Neuromodulation, Kurzzeit- und Langzeit-Plastizität der Stärke der synaptischen Übertragung an der hippokampalen Moosfaser-Synapse erarbeitet. Die vorgestellten Daten konnten mit Hilfe von in vitro experimentellen Ansätzen an der hippokampalen Formation von Mäusen gewonnen werden und durch Analysen und Simulationen aus dem Bereich der theoretischen Biologie bestätigt und erweitert werden.Chemical synapses are key elements for the communication between nerve cells. This communication can be regulated on various time scales and through different mechanisms affecting synaptic transmission. Amongst these are slow and long-lasting adjustments by endogenous neuromodulators, instantaneous and reversible activity-dependent regulation by short-term plasticity and persistent activity-dependent changes by long-term plasticity. Within this thesis, we have investigated several aspects of modulation of synaptic transmission and its functional relevance at the example of the hippocampal mossy fiber synapse. The presented results were acquired through electrophysiological and microfluorometric experiments at the hippocampal formation of mice and could be verified and substantiated through theoretical analyses, simulations and computational modelling

Different regulation of Purkinje cell dendritic development in cerebellar slice cultures by protein kinase Calpha and -beta

Activity of protein kinase C (PKC), and in particular the PKCgamma-isoform, has been shown to strongly affect and regulate Purkinje cell dendritic development, suggesting an important role for PKC in activity-dependent Purkinje cell maturation. In this study we have analyzed the role of two additional Ca(2+)-dependent PKC isoforms, PKCalpha and -beta, in Purkinje cell survival and dendritic morphology in slice cultures using mice deficient in the respective enzymes. Pharmacological PKC activation strongly reduced basal Purkinje cell dendritic growth in wild-type mice whereas PKC inhibition promoted branching. Purkinje cells from mice deficient in PKCbeta, which is expressed in two splice forms by granule but not Purkinje cells, did not yield measurable morphological differences compared to respective wild-type cells under either experimental condition. In contrast, Purkinje cell dendrites in cultures from PKCalpha-deficient mice were clearly protected from the negative effects on dendritic growth of pharmacological PKC activation and showed an increased branching response to PKC inhibition as compared to wild-type cells. Together with our previous work on the role of PKCgamma, these data support a model predicting that normal Purkinje cell dendritic growth is mainly regulated by the PKCgamma-isoform, which is highly activated by developmental processes. The PKCalpha isoform in this model forms a reserve pool, which only becomes activated upon strong stimulation and then contributes to the limitation of dendritic growth. The PKCbeta isoform appears to not be involved in the signaling cascades regulating Purkinje cell dendritic maturation in cerebellar slice cultures

Place field specific spiking activity of dentate gyrus granule cells triggers long-term potentiation of mossy fiber synaptic responses <i>in vitro</i>.

<p>(<b>A</b>) Presentation of spike train 1 (indicated by grey area) led to potentiation of mossy fiber fEPSP amplitudes in this examplary recording. Constant stimulation frequency before and after delivery of spike train was 0.05 Hz. Application of DCGIV at the end of experiment blocked mossy fiber synaptic transmission. Upper traces show averages of 10 sweeps under control condition and 30 min after presentation of spike train 1. (<b>B</b>) Summary of n = 5 such experiments. Presentation of spike train led to reliable long-term potentiation of fEPSP amplitudes to ∼130% of control values 25 min after spike train 1. (<b>C</b>) Time-resolved plot of another place field specific spike episode (spike train 2, up) and continuous recording of mossy fiber fEPSP response to single presentation of this spike train (lower part). Stimulus artifacts are cut for visual clarity. Please note different timescale compared to spike train 1. (<b>D</b>) Examplary mossy fiber synaptic fEPSP recording, where a single presentation of spike train 2 (grey bar, not drawn to scale) leads to long-term potentiation of fEPSP responses. Arrow points to frequency facilitation paradigm (switch of stimulation frequency from 0.05 Hz to 1 Hz for 20 stimuli). Application of DCGIV (1 µM) at the end of experiment blocked mossy fiber fEPSPs. Upper traces show averages of 10 sweeps each under control condition and 25 minutes after presentation of spike train. Constant stimulation frequency was 0.05 Hz. (<b>E</b>) Repetitive presentation of spike train 2 (5x with 30 s pauses inbetween) resulted in pronounced long-term potentiation of mossy fiber fEPSP amplitudes in this examplary experiment. Upper traces show averages of 10 sweeps each under control condition and 25 minutes after repetitive presentation of spike train. (<b>F</b>) Summary of n = 6 experiments with single presentation of spike train (open circles) and n = 7 experiments with repetitive presentation (filled circles). Both paradigms led to significant long-term potentiation of response amplitudes to ∼150% and ∼230% of control values, respectively. Data shows mean ± sem. Upper dashed lines in subpanels indicate basal response amplitudes to constant stimulation at 0.05 Hz.</p

Natural spike trains induce mossy fiber LTP indepedent of NMDAR and mGluR activation.

<p>(<b>A</b>) Exemplary mossy fiber fEPSP recording under blockage of NMDA- and mGlu-receptors. Repetitive presentation of spike train 2 still induced significant long-term potentiation. Arrow points to frequency facilitation paradigm. Upper traces are averages of 10 sweeps each under control condition and 25 min after presentation of spike trains. Constant stimulation frequency was 0.05 Hz. (<b>B</b>) Summary of n = 6 such experiments and experiments under control conditions, respectively. Repetitive presentation of spike train 2 resulted in potentiation of response amplitudes to ∼220% of control values 30 min after presentation of spike trains. Data was binned to 1 min time points and depicts mean ± sem. Upper dashed lines in subpanels indicate basal response amplitudes to constant stimulation at 0.05 Hz.</p

Natural spike train induced long-term potentiation is strongly reduced in the presence of elevated cAMP levels.

<p>(<b>A</b>) Application of the adenylate cyclase activator forskolin (50 µM) enhances synaptic transmission in this exemplary experiment and strongly reduces long-term potentiation induced by repetitive (5 x) delivery of spike train 2. Traces on top are averages of five consecutive sweeps taken at the time point indicated by the numbers in the graph. Triangle denotes frequency facilitation paradigm for 20 pulses with 1 Hz, arrow indicates time point of spike train 2 application, second horizontal bar represents application of DCGIV (1 µM) at the end of experiment. (<b>B</b>) Summary plot displaying the drastically reduced potentiation for n = 4 such experiments (closed circles). Values are normalized to the amplitude in forskolin before train delivery. For comparison, the potentiation elicited by spike train 2 in the absence of drugs (open circles, same dataset as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009961#pone-0009961-g002" target="_blank">Figure 2F</a>) is overlayed. In the presence of forskolin the potentiation was reduced to 143.4±11.5% (p<0.001, compared to control).</p

Mossy fiber synaptic LTP - induced by place field specific spiking activity of dentate gyrus granule cells - is presynaptically expressed.

<p>(<b>A</b>) Examplary whole-cell recording of mossy fiber synaptic responses in CA3 pyramidal cell. Repetitive presentation of spike train 2 (grey bars, compare <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009961#pone-0009961-g002" target="_blank">Figure 2</a>) induces long-term potentiation of EPSC amplitudes. Upper traces show averages of 10 sweeps each under control condition and 20 min after presentation of spike train. Constant stimulation frequency outside of spike train 2 was 0.1 Hz. CA3 pyramidal cell was held in voltage-clamp condition at -60 mV, also during presentation of spike train. Upper dashed line indicates basal response amplitudes to constant stimulation at 0.1 Hz. (<b>B</b>) Summary of n = 5 whole-cell experiments where repetitive presentation of spike train 2 induces long-term potentiation of mossy fiber EPSC amplitudes. Potentiation to ∼220% of control values was visible 30 min after spike train. Data was binned to 0.5 min time points and depicts mean ± sem. (<b>C</b>) CV² analysis of data from experiments in A. The change in the squared coefficient of variation in control versus LTP condition shows a linear dependence on the change in the mean response amplitude. (<b>D</b>) The mean rate of failures of synaptic transmission is decreased after expression of LTP. Upper traces show 50 individual sweeps (grey) and mean sweeps (black) in control and LTP condition of an exemplary whole-cell recording. Note the large incidence of synaptic failures under control conditions.</p