Marina Chistiakova

Modification of discharge patterns of neocortical neurons by induced oscillations of the membrane potential

We investigated, with whole-cell recordings from rat visual cortex slices, how sinusoidal modulation of the membrane potential affects signal transmission. Subthreshold oscillations activate tetrodotoxin sensitive, transient inward currents whose threshold, phase lag and duration change with modulation frequency. These periodically recurring phases of enhanced excitability affect synaptic transmission in two ways. Weak and short lasting excitatory postsynaptic potentials evoke discharges only if they are coincident within a few milliseconds with these active membrane responses. Long-lasting, N-methyl-D-aspartate-mediated or polysynaptic excitatory postsynaptic potentials, by contrast, evoke trains of spikes, that are precisely time-locked to the oscillations and may last for more than 100 ms. Thus, oscillations impose a precise temporal window for the integration of synaptic inputs, favouring coincidence detection and they generate temporally-structured responses whose timing and amplitude are largely independent of the input. These properties are ideally suited for the synchronization of neuronal activity and the encoding of information in the precise timing of discharges. A preliminary account of these data has appeared in an abstract form [Volgushev M. et al. (1995) Eur. J Neurosci. 8, 77].

Membrane properties and spike generation in rat visual cortical cells during reversible cooling

We studied the effects of reversible cooling between 35 and 7 °C on membrane properties and spike generation of cells in slices of rat visual cortex. Cooling led to a depolarization of the neurones and an increase of the input resistance, thus bringing the cells closer to spiking threshold. Excitability, measured with intracellular current steps, increased with cooling. Synaptic stimuli were most efficient in producing spikes at room temperature, but strong stimulation could evoke spikes even below 10 °C. Spike width and total area increased with cooling, and spike amplitude was maximal between 12 and 20 °C. Repetitive firing was enhanced in some cells by cooling to 20–25 °C, but was always suppressed at lower temperatures. With cooling, passive potassium conductance decreased and the voltage‐gated potassium current had a higher activation threshold and lower amplitude. At the same time, neither passive sodium conductance nor the activation threshold of voltage‐dependent sodium channels changed. Therefore changing the temperature modifies the ratio between potassium and sodium conductances, and thus alters basic membrane properties. Data from two cells recorded in slices of cat visual cortex suggest a similar temperature dependence of the membrane properties of neocortical neurones to that described above in the rat. These results provide a framework for comparison of the data recorded at different temperatures, but also show the limitations of extending the conclusions drawn from in vitro data obtained at room temperature to physiological temperatures. Further, when cooling is used as an inactivation tool in vivo, it should be taken into account that the mechanism of inactivation is a depolarization block. Only a region cooled below 10 °C is reliably silenced, but it is always surrounded by a domain of hyperexcitable cells.

Synaptic Transmission in the Neocortex during Reversible Cooling

We studied the effects of reversible cooling on synaptic transmission in slices of rat visual cortex. Cooling had marked monotonic effects on the temporal properties of synaptic transmission. It increased the latency of excitatory postsynaptic potentials and prolonged their time-course. Effects were non-monotonic on other properties, such as amplitude of excitatory postsynaptic potentials and generation of spikes. The amplitude of excitatory postsynaptic potentials increased, decreased, or remain unchanged while cooling down to about 20 degrees C, but thereafter it declined gradually in all cells studied. The effect of moderate cooling on spike generation was increased excitability, most probably due to the ease with which a depolarized membrane potential could be brought to spike threshold by a sufficiently strong excitatory postsynaptic potential. Stimuli that were subthreshold above 30 degrees C could readily generate spikes at room temperature. Only at well below 10 degrees C could action potentials be completely suppressed. Paired-pulse facilitation was less at lower temperatures, indicating that synaptic dynamics are different at room temperature as compared with physiological temperatures. These results have important implications for extrapolating in vitro data obtained at room temperatures to higher temperatures. The data also emphasize that inactivation by cooling might be a useful tool for studying interactions between brain regions, but the data recorded within the cooled area do not allow reliable conclusions to be drawn about neural operations at normal temperatures.

Relations Between Long‐term Synaptic Modifications and Paired‐pulse Interactions in the Rat Neocortex

The phenomenon of paired‐pulse facilitation (PPF) was exploited to investigate the role of presynaptic mechanisms in the induction and maintenance of long‐term synaptic plasticity in the neocortex. Long‐term potentiation (LTP) and depression (LTD) were induced without afferent activation by applying tetani of intracellular pulses. Our results show that synaptic modifications closely resembling LTP and LTD can be induced by postsynaptic activation alone. The polarity of these synaptic modifications depends on initial properties of the input, as indicated by a correlation between initial PPF ratio and post‐tetanic amplitude changes: inputs exhibiting strong PPF, which might be associated with low release probability tend to be potentiated, while inputs with small PPF are more likely to show depression. Maintenance of both LTP and LTD involve presynaptic mechanisms, as indicated by changes in PPF ratios and in failure rate after LTP or LTD induction. Presynaptic mechanisms could include changes in release probability and/or in the number of active release sites. Because induction was postsynaptic, this supports the notion of a retrograde signal. The relative contribution of pre‐ and postsynaptic mechanisms in the maintenance of long‐term synaptic modifications depends on the initial state of the synaptic input and on LTP magnitude. PPF changes were especially pronounced in inputs which had initially high PPF and underwent strong potentiation. Since LTP and LTD are associated with changes of PPF ratios these synaptic modifications do not only alter the gain but also the temporal properties of synaptic transmission. Because of the LTP associated reduction of PPF, potentiated inputs profit less from temporal summation, favouring transmission of synchronized, low frequency activity.

Heterosynaptic plasticity in the neocortex

Ongoing learning continuously shapes the distribution of neurons’ synaptic weights in a system with plastic synapses. Plasticity may change the weights of synapses that were active during the induction—homosynaptic changes, but also may change synapses not active during the induction—heterosynaptic changes. Here we will argue, that heterosynaptic and homosynaptic plasticity are complementary processes, and that heterosynaptic plasticity might accompany homosynaptic plasticity induced by typical pairing protocols. Synapses are not uniform in their susceptibility for plastic changes, but have predispositions to undergo potentiation or depression, or not to change. Predisposition is one of the factors determining the direction and magnitude of homo- and heterosynaptic changes. Heterosynaptic changes which take place according to predispositions for plasticity may provide a useful mechanism(s) for homeostasis of neurons’ synaptic weights and extending the lifetime of memory traces during ongoing learning in neuronal networks.

ALL-OR-NONE EXCITATORY POSTSYNAPTIC POTENTIALS IN THE RAT VISUAL CORTEX

Intracellular recordings were obtained from supragranular neurons in slices of the rat visual cortex. In ∼25% of the cells large (0.5–1.6 mV) excitatory postsynaptic potentials (EPSPs) of constant amplitude were observed after minimal, presumably single‐fibre stimulation. The amplitude variance of these large EPSPs was surprisingly small and within the range of the variance of the noise. These EPSPs could be reduced in amplitude by paired‐pulse and low‐frequency stimulation or by raising extracellular Mg2+ concentration. Reduced EPSPs could either continue to behave as all‐or‐none responses, or they could fluctuate between several amplitude levels. Conversely, responses where the amplitude fluctuated from trial to trial under control conditions could be converted into large all‐or‐none responses by paired‐pulse facilitation. This indicates that the large all‐or‐none EPSPs were composed of several subunits, probably reflecting the action of several different release sites. It is concluded that these release sites are either independent and operate with a probability close to 1 or, if operating with a lower probability, are coordinated by a mechanism which synchronizes release. Several observations suggest that release probabilities can switch from values close to 1 to 0 with repetitive stimulation or high Mg2+ concentration. Thus, a substantial fraction of single‐fibre inputs to supragranular cells possess synapses which operate with high synaptic efficiency and extremely low variance under control conditions but can undergo drastic changes in efficacy when release probabilities are interfered with. Such modifications of release probability could serve as an effective mechanism to regulate the gain of synaptic transmission.

Retrograde signalling with nitric oxide at neocortical synapses.

Long‐term changes of synaptic transmission in slices of rat visual cortex were induced by intracellular tetanization: bursts of short depolarizing pulses applied through the intracellular electrode without concomitant presynaptic stimulation. Long‐term synaptic changes after this purely postsynaptic induction were associated with alterations of release indices, thus providing a case for retrograde signalling at neocortical synapses. Both long‐term potentiation and long‐term depression were accompanied by presynaptic changes, indicating that retrograde signalling can achieve both up‐ and down‐regulation of transmitter release. The direction and the magnitude of the amplitude changes induced by a prolonged intracellular tetanization depended on the initial properties of the input. The inputs with initially high paired‐pulse facilitation (PPF) ratio, indicative of low release probability, were most often potentiated. The inputs with initially low PPF ratio, indicative of high release probability, were usually depressed or did not change. Thus, prolonged postsynaptic activity can lead to normalization of the weights of nonactivated synapses. The dependence of polarity of synaptic modifications on initial PPF disappeared when plastic changes were induced with a shorter intracellular tetanization, or when the NO signalling pathway was interrupted by inhibition of NO synthase activity or by application of NO scavengers. This indicates that the NO‐dependent retrograde signalling system has a relatively high activation threshold. Long‐term synaptic modifications, induced by a weak postsynaptic challenge or under blockade of NO signalling, were nevertheless associated with presynaptic changes. This suggests the existence of another retrograde signalling system, additional to the high threshold, NO‐dependent system. Therefore, our data provide a clear case for retrograde signalling at neocortical synapses and indicate that multiple retrograde signalling systems, part of which are NO‐dependent, are involved.

Heterosynaptic Plasticity Multiple Mechanisms and Multiple Roles

Plasticity is a universal property of synapses. It is expressed in a variety of forms mediated by a multitude of mechanisms. Here we consider two broad kinds of plasticity that differ in their requirement for presynaptic activity during the induction. Homosynaptic plasticity occurs at synapses that were active during the induction. It is also called input specific or associative, and it is governed by Hebbian-type learning rules. Heterosynaptic plasticity can be induced by episodes of strong postsynaptic activity also at synapses that were not active during the induction, thus making any synapse at a cell a target to heterosynaptic changes. Both forms can be induced by typical protocols used for plasticity induction and operate on the same time scales but have differential computational properties and play different roles in learning systems. Homosynaptic plasticity mediates associative modifications of synaptic weights. Heterosynaptic plasticity counteracts runaway dynamics introduced by Hebbian-type rules and balances synaptic changes. It provides learning systems with stability and enhances synaptic competition. We conclude that homosynaptic and heterosynaptic plasticity represent complementary properties of modifiable synapses, and both are necessary for normal operation of neural systems with plastic synapses.

Heterosynaptic Plasticity Prevents Runaway Synaptic Dynamics

Spike timing-dependent plasticity (STDP) and other conventional Hebbian-type plasticity rules are prone to produce runaway dynamics of synaptic weights. Once potentiated, a synapse would have higher probability to lead to spikes and thus to be further potentiated, but once depressed, a synapse would tend to be further depressed. The runaway synaptic dynamics can be prevented by precisely balancing STDP rules for potentiation and depression; however, experimental evidence shows a great variety of potentiation and depression windows and magnitudes. Here we show that modifications of synapses to layer 2/3 pyramidal neurons from rat visual and auditory cortices in slices can be induced by intracellular tetanization: bursts of postsynaptic spikes without presynaptic stimulation. Induction of these heterosynaptic changes depended on the rise of intracellular calcium, and their direction and magnitude correlated with initial state of release mechanisms. We suggest that this type of plasticity serves as a mechanism that stabilizes the distribution of synaptic weights and prevents their runaway dynamics. To test this hypothesis, we develop a cortical neuron model implementing both homosynaptic (STDP) and heterosynaptic plasticity with properties matching the experimental data. We find that heterosynaptic plasticity effectively prevented runaway dynamics for the tested range of STDP and input parameters. Synaptic weights, although shifted from the original, remained normally distributed and nonsaturated. Our study presents a biophysically constrained model of how the interaction of different forms of plasticity—Hebbian and heterosynaptic—may prevent runaway synaptic dynamics and keep synaptic weights unsaturated and thus capable of further plastic changes and formation of new memories.

Induction of LTP and LTD in visual cortex neurones by intracellular tetanization.

Neurones from supragranular layers of rat visual cortex slices were activated by intracellular tetanization (IT) without concomitant presynaptic stimulation. The effect of IT was examined on EPSPs evoked at low stimulation intensity from two subsets of afferents by electrodes positioned in layers II and IV, respectively. In 17 of 23 inputs to 15 cells IT led to changes in EPSP amplitudes which persisted throughout the recording period (from at least 40 min to 3 h). For 10 potentiated inputs (nine cells) and eight depressed inputs (seven cells), EPSP amplitudes measured 30 min after tetanization were 167 ± 14% and 55 ± 14% of the pretetanic controls, respectively. In seven cells both inputs changed, in five cases modifications were of the opposite and in two cases of the same polarity.