Induction Of Long-term Plasticity Research Articles

Interneuron-specific plasticity at parvalbumin and somatostatin inhibitory synapses onto CA1 pyramidal neurons shapes hippocampal output

The formation and maintenance of spatial representations within hippocampal cell assemblies is strongly dictated by patterns of inhibition from diverse interneuron populations. Although it is known that inhibitory synaptic strength is malleable, induction of long-term plasticity at distinct inhibitory synapses and its regulation of hippocampal network activity is not well understood. Here, we show that inhibitory synapses from parvalbumin and somatostatin expressing interneurons undergo long-term depression and potentiation respectively (PV-iLTD and SST-iLTP) during physiological activity patterns. Both forms of plasticity rely on T-type calcium channel activation to confer synapse specificity but otherwise employ distinct mechanisms. Since parvalbumin and somatostatin interneurons preferentially target perisomatic and distal dendritic regions respectively of CA1 pyramidal cells, PV-iLTD and SST-iLTP coordinate a reprioritisation of excitatory inputs from entorhinal cortex and CA3. Furthermore, circuit-level modelling reveals that PV-iLTD and SST-iLTP cooperate to stabilise place cells while facilitating representation of multiple unique environments within the hippocampal network.

Disabling Gβγ-SNAP-25 interaction in gene-targeted mice results in enhancement of long-term potentiation at Schaffer collateral-CA1 synapses in the hippocampus.

Three SNARE proteins, SNAP-25, syntaxin 1A, and VAMP2 or synaptobrevin 2, constitute the minimal functional machinery needed for the regulated secretion of neurotransmitters. Dynamic changes in the regulated release of neurotransmitters are associated with the induction of long-term plasticity at central synapses. In-vitro studies have validated the C-terminus of SNAP-25 as a target for inhibitory Gi/o-coupled G-protein coupled receptors at a number of synapses. The physiological consequences of the interaction between Gi/o proteins and SNAP-25 in the context of activity-dependent long-term synaptic plasticity are not well understood. Here, we report direct ex-vivo evidence of the involvement of the C-terminus of SNAP-25 in inducing long-term potentiation of synaptic strength at Schaffer collateral-CA1 synapses using a gene-targeted mouse model with truncated C-terminus (carboxyl terminus) of SNAP-25. It has been shown previously that truncation of the three extreme C-terminal residues in SNAP-25[INCREMENT]3 homozygote mice reduces its interaction with the inhibitory Gβγ subunits two-fold. In in-vitro hippocampal slices, we show that these SNAP-25[INCREMENT]3 mice express significantly larger magnitude of long-term potentiation at hippocampal Schaffer collateral-CA1 synapses.

Adenosine A2A Receptors Control Glutamatergic Synaptic Plasticity in Fast Spiking Interneurons of the Prefrontal Cortex.

Adenosine A2A receptors (A2AR) are activated upon increased synaptic activity to assist in the implementation of long-term plastic changes at synapses. While it is reported that A2AR are involved in the control of prefrontal cortex (PFC)-dependent behavior such as working memory, reversal learning and effort-based decision making, it is not known whether A2AR control glutamatergic synapse plasticity within the medial PFC (mPFC). To elucidate that, we tested whether A2AR blockade affects long-term plasticity (LTP) of excitatory post-synaptic potentials in pyramidal neurons and fast spiking (FS) interneurons in layer 5 of the mPFC and of population spikes. Our results show that A2AR are enriched at mPFC synapses, where their blockade reversed the direction of plasticity at excitatory synapses onto layer 5 FS interneurons from LTP to long-term depression, while their blockade had no effect on the induction of LTP at excitatory synapses onto layer 5 pyramidal neurons. At the network level, extracellularly induced LTP of population spikes was reduced by A2AR blockade. The interneuron-specificity of A2AR in controlling glutamatergic synapse LTP may ensure that during periods of high synaptic activity, a proper excitation/inhibition balance is maintained within the mPFC.

Temporal dynamics of cerebellar and motor cortex physiological processes during motor skill learning

Learning motor tasks involves distinct physiological processes in the cerebellum (CB) and primary motor cortex (M1). Previous studies have shown that motor learning results in at least two important neurophysiological changes: modulation of cerebellar output mediated in-part by long-term depression of parallel fiber-Purkinje cell synapse and induction of long-term plasticity (LTP) in M1, leading to transient occlusion of additional LTP-like plasticity. However, little is known about the temporal dynamics of these two physiological mechanisms during motor skill learning. Here we use non-invasive brain stimulation to explore CB and M1 mechanisms during early and late motor skill learning in humans. We predicted that early skill acquisition would be proportional to cerebellar excitability (CBI) changes, whereas later stages of learning will result in M1 LTP-like plasticity modifications. We found that early, and not late into skill training, CBI changed. Whereas, occlusion of LTP-like plasticity over M1 occurred only during late, but not early training. These findings indicate a distinct temporal dissociation in the physiological role of the CB and M1 when learning a novel skill. Understanding the role and temporal dynamics of different brain regions during motor learning is critical to device optimal interventions to augment learning.

The synchronous and reciprocal regulation of the activities of cysteine proteases associated with long-term plasticity

Using hippocampal slices from Wistar rats, we studied the correlation between modifications of the activities of cysteine proteases in various models of long-term plasticity. CA3-CA1 long-term depression (LTD) was induced according to the standard procedure by low-frequency stimulation (1 Hz, 900 impulses). Long-term potentiation (LTP) was induced by high-frequency stimulation (HFS) of Schaffer collaterals (100 Hz, 1 s) and followed by a 1-h recording. After the end of the experiments, the slices were immediately frozen at −70°C and the activities of caspase-3 and calpain were measured in each slice separately. We hypothesized that increased intracellular calcium content associated with long-term plasticity may be accompanied by synchronous regulation of these proteases. Complex study of the proteolytic activities of caspase-3 and calpain supported our hypothesis that long-term plasticity is accompanied by changes in their balance; however, these changes were specific for each type of plasticity. We did not find any correlation between caspase-3 and calpain activities in the passive control slices, which were not electrically stimulated. However, the activities of these enzymes correlated after stimulation of Schaffer collaterals using all protocols of the induction of long-term plasticity. We observed a positive correlation between the activities of caspase-3 and calpain after the induction of LTD or depotentiation. This effect was probably due to caspase-dependent proteolysis of calpastatin, a natural inhibitor of calpain. In contrast, in slices with LTP maintenance for 1 h after HFS, this correlation was inversed. This fact poorly conforms to the initial hypothesis. Possible mechanisms that underlie the inversion of the ratio of activation of cysteine proteases are discussed.

Immediate early genes expression in the cerebellar cortex correlates with LTP and LTD induction

The consolidation of changes following activity-dependent neural plasticity are believed to involve specific patterns of gene expression. In the hippocampus, immediate early genes are thought to contribute to long-term synaptic plasticity (LTP and LTD); this phenomenon may occur also in the cerebellum, in which the transcription factors c-Fos and P-CREB have been identified. The cerebellum granular layer (GL) can manifest both LTP and LTD following a Theta Burst Stimulus (TBS) delivered to the mossy fibers. We have employed VSD imaging in rat cerebellar slices (P18-24) in order to map the spatial distribution of LTP and LTD in the cerebellum GL. Fluorescence changes were correlated to LTP or LTD in two different post-TBS time ranges (15 and 120 min). Slices were then fixed and processed for immunohistochemistry in order to identify levels of c-Fos and P-CREB expression. The induction of long-term plasticity increased the average level of P-CREB both at 15 min (+39±4.9, p<0.01%) and 120 min (+24±7.2, p<0.05%) after TBS. The level of c-Fos was unaltered at 15 min, while it significantly increased at 120 min (+37±8.9, p<0.05%). By spatially correlating longterm synaptic plasticity with the corresponding variation of P-CREB and c-Fos, we observed that regions showing LTP well correlated (p<0.05) with positive variations of P-CREB and c-Fos. Conversely, areas showing LTD correlated exclusively (p<0.05) with negative variations of P-CREB. Slices were also evaluated by in situ hybridization and a similar analysis was performed. The levels of fos and CREB mRNA expression and their spatial correlation with the sign of long-term synaptic plasticity corresponded with the immunohistochemical results. As a further test, VSD recordings showed that the induction of granular layer LTP and LTD could be prevented by applying 50 mM D-APV, a selective NMDA receptor blocker. Moreover, in situ hybridization and immunohistochemistry analysis evidenced that in these conditions both mRNA and protein expression levels of c-fos and CREB were unchanged, confirming the involvement of these two transcription factors in cerebellar granular layer plasticity.

Interactions between short-term and long-term plasticity: shooting for a moving target

AbstractFar from being static transmission units, synapses are highly dynamical elements that change over multiple time scales depending on the history of the neural activity of both the pre- and postsynaptic neuron. Moreover, synaptic changes on different time scales interact: long-term plasticity (LTP) can modify the properties of short-term plasticity (STP) in the same synapse. Most existing theories of synaptic plasticity focus on only one of these time scales (either STP or LTP or late-LTP) and the theoretical principles underlying their interactions are thus largely unknown. Here we develop a normative model of synaptic plasticity that combines both STP and LTP and predicts specific patterns for their interactions. Recently, it has been proposed that STP arranges for the local postsynaptic membrane potential at a synapse to behave as an optimal estimator of the presynaptic membrane potential based on the incoming spikes. Here we generalize this approach by considering an optimal estimator of a non-linear function of the membrane potential and the long-term synaptic efficacy -- which itself may be subject to change on a slower time scale. We find that an increase in the long-term synaptic efficacy necessitates changes in the dynamics of STP. More precisely, for a realistic non-linear function to be estimated, our model predicts that after the induction of LTP, causing long-term synaptic efficacy to increase, a depressing synapse should become even more depressing. That is, in a protocol using trains of presynaptic stimuli, as the initial EPSP becomes stronger due to LTP, subsequent EPSPs should become weakened and this weakening should be more pronounced with LTP. This form of redistribution of synaptic efficacies agrees well with electrophysiological data on synapses connecting layer 5 pyramidal neurons.

Spino‐dendritic cross‐talk in rodent Purkinje neurons mediated by endogenous Ca2+‐binding proteins

The range of actions of the second messenger Ca(2+) is a key determinant of neuronal excitability and plasticity. For dendritic spines, there is on-going debate regarding how diffusional efflux of Ca(2+) affects spine signalling. However, the consequences of spino-dendritic coupling for dendritic Ca(2+) homeostasis and downstream signalling cascades have not been explored to date. We addressed this question by four-dimensional computer simulations, which were based on Ca(2+)-imaging data from mice that either express or lack distinct endogenous Ca(2+)-binding proteins. Our simulations revealed that single active spines do not affect dendritic Ca(2+) signalling. Neighbouring, coactive spines, however, induce sizeable increases in dendritic [Ca(2+)](i) when they process slow synaptic Ca(2+) signals, such as those implicated in the induction of long-term plasticity. This spino-dendritic coupling is mediated by buffered diffusion, specifically by diffusing calbindin-bound Ca(2+). This represents a central mechanism for activating calmodulin in dendritic shafts and therefore a novel form of signal integration in spiny dendrites.

Selective involvement of opioids in the mechanisms of synapse-specific plasticity in the common snail during the acquisition of sensitization

Studies on defensive behavior command neurons LP11 and RP11 in semi-intact common snail preparations were performed to investigate the effects of the opioid peptide met-enkephalin and the opioid antagonist naloxone on the effects of nociceptive sensitization. Application of nociceptive stimuli to the snail's head elicited marked reversible membrane depolarization along with depression of neuron responses to sensory stimulation during the short-term stage of sensitization and facilitation of responses in the long-term stage. Met-enkephalin at a dose of 10 microM but not at a dose of 0.1 microM partially suppressed responses to nociceptive stimuli. Acquisition of sensitization during exposure to met-enkephalin at doses of 10 and 0.1 microM led to complete suppression of the facilitation of responses to tactile stimulation of the head. Facilitation of responses to chemical stimulation of the head and tactile stimulation of the foot in these conditions was similar to that of neurons in control sensitized animals. Acquisition of sensitization during exposure to met-enkephalin and/or naloxone elicited selective suppression of facilitation of responses to chemical stimulation of the head but had no effect on facilitation of responses to tactile stimulation of the head and foot. Met-enkephalin and naloxone had no effect on the depression of neuron responses evoked by sensory stimulation in the short-term stage of sensitization. It is suggested that during the acquisition of sensitization in the common snail, opioids are involved in controlling the mechanism of nociception and in the mechanisms of selective induction of long-term plasticity of the synaptic inputs to command neurons activated by tactile and chemical stimulation of the animal's head.