Discuss how the postsynaptic calcium signal can be necessary for both LTD and LTP

Discuss how the postsynaptic calcium signal can be necessary for both LTD and LTP

 

Long-term potentiation (LTP) and long-term depression (LTD) describe the activity-dependent changes in synaptic efficacy that can be observed in multiple brain regions. Discovered first by (Bliss & Lomo, 1973) and (Dudek & Bear, 1992) respectively, they enable synaptic transmission to be increased or decreased. This, in conjunction with the fact that they can be rapidly induced, long-lasting and display properties of input specificity and cooperativity, makes them prime candidates as cellular correlates of learning and memory encoding, and as such they have been studied extensively. One aspect of synaptic plasticity that is important to consider is how cortical neurons are able to exhibit both LTP and LTD depending on the conditioning protocols that are applied to them. In this essay, I will discuss the mechanisms of induction for each, the proteins involved, and how both processes can occur in parallel without occurring in conflict.

 

LTP and LTD are induced by specific, and different, patterns of activity. LTP is induced by either high-frequency stimulation (tetanic stimulation) of the presynaptic neuron (resulting in strong temporal summation of EPSPs in the postsynaptic terminal), low frequency-stimulation of the axon of a cell held at a strongly depolarised membrane potential (typically -10mV, called the pairing protocol), or precisely timed stimulation of the presynaptic neuron followed by the postsynaptic neuron (within 10ms). Any of these three protocols results in strong postsynaptic depolarisation, maximal activation of postsynaptic NMDA receptors, and thus maximal NMDAR-dependent influx of Ca²⁺. LTD, on the other hand, is induced by low-frequency stimulation of the presynaptic neuron (resulting in modest postsynaptic depolarisation), the low-frequency stimulation of the axon of a cell held at a modestly depolarised membrane potential, or the precisely timed stimulation of the postsynaptic neuron followed with the presynaptic neuron (within 10ms). Any of these three protocols results in modest postsynaptic depolarisation and thus modest but prolonged increase in postsynaptic [Ca²⁺]. Thus, it appears that both LTP and LTD are reliant on an NMDAR-dependent postsynaptic Ca²⁺ influx, and indeed a number of studies have shown this. In experiments on rat CA1 slices, Collingridge et al (1983) showed that application of AP5 inhibits the induction of LTP without altering the performance of the synapse, whilst Malenka et al (1988) used Nitr-5 (a photolabile calcium chelator) to show that postsynaptic Ca²⁺ is both necessary and sufficient to induce LTP. Microflourometric measurements in individual CA1 pyramidal cells during LTP induction showed that high-frequency stimulus trains produce a transient components of postsynaptic Ca²⁺ accumulation that is blocked by AP5, indicating that LTP-induction protocol induce an NMDAR-dependent increase in intracellular Ca²⁺ (Regehr & Tank, 1990). The same dependence on NMDAR-mediated Ca²⁺ influx for LTD induction was shown by Mulkey and Malenka (1992) in their experiments in CA1 cells using BAPTA (a calcium chelator). Thus, we see that both LTP and LTD induction depends on an NMDAR-mediated postsynaptic influx of Ca²⁺.

 

However, this creates a problem: how is it possible that neurons are able to undergo both LTP and LTD depending on different conditioning stimuli protocols if both processes are input specific and NMDAR-dependent? The BCM Theory (put forward by Bienenstock, Cooper, and Munro in 1982) aims to provide a solution to this problem. It posits that the bidirectional control of synaptic strength depends on some combined function of pre- and postsynaptic activity, and proposes a sliding threshold for LTP or LTD induction. This modification threshold, _m, could adjust as a function of the history of average activity in the postsynaptic neuron (see figure 1). Lisman (1989) took this one step further by suggesting that the bidirectional control relies specifically on increases of postsynaptic [Ca²⁺] to different levels. Indeed, experiments have shown that modest increases in [Ca²⁺] triggers LTD, whilst stronger increases are required to trigger LTP. Although it may seem paradoxical that intracellular increases in free Ca²⁺ can lead to both LTP and LTD, this observation can be reconciled by two primary observations. Firstly, the time course and magnitude of Ca²⁺ elevations can differ dramatically. Yang, Tany and Zucker (1999) showed that LTD induction can occur with modest (0.7M) but enduring (60s) Ca²⁺ elevation, whilst LTP induction can occur with high () but brief (3s) Ca²⁺ elevation. Secondly, Ca²⁺-sensitive enzymes at the synapse vary greatly in their Ca²⁺ affinity. Thus, the kinetics and magnitude of Ca²⁺ signal can initiate markedly different biochemical cascades.

Lisman (1989) incorporated the above observations into a model that suggest that LTD induction is a consequence of the activation of protein phosphatases at low [Ca²⁺], whilst LTP is a consequence of a shift towards protein kinase activity that occurs at higher [Ca²⁺] (see figure 2). Indeed, there is much experimental support for the basics tenets of this model. Malenka et al, (1989) found that intracellular injection of H-7 (protein kinase inhibitor) into CA1 pyramidal cells blocks LTP induction, indicating the necessity of kinase activity for LTP. Further experiments by Malinow et al, (1989), showed that postsynaptic PKC and CaMKII are required for induction of LTP, and Lledo et al, (1995), showed that the injection of a truncated, constitutively active form of CaMKII into CA1 pyramidal cells is sufficient for synaptic strength augmentation. Evidence suggests that CaMKII acts to induce LTP by phosphorylation of AMPARs (thus increasing their conductance, Benke et al, 1998) and by acting to bring about the insertion of AMPARs at the synapse. Conversely, there is significant evidence to suggest that LTD is a consequence of the dephosphorylation and internalisation of AMPARs. Lee et al, (1998), used phosphorylation site-specific antibodies to show that the induction of LTD produces a persistent dephosphorylation of the GluR1 subunit of AMPARs. Furthermore, Mulkey et al (1993) showed that extracellular application of okadaic acid or calyculin A (inhibitors of phosphatases 1 and 2A, PP1 and PP2A) blocked LTD, implicating that phosphatase activity is required for LTD induction. However, until this point the mechanism by which PP1 or PP2A was regulated by synaptic activity was unclear as these phosphatases are not directly influenced by [Ca²⁺]. It was postulated that a more complex phosphatase cascade consisting of calcineurin, inhibitor-1 and PP1 was required, and in 1994, Mulkey et al provided evidence in support of this. In addition, experiments have shown that cAMP plays a role in regulating LTP/LTD induction. High intracellular [Ca²⁺] activated adenylyl cycles, which increases intracellular cAMP levels, resulting in the activation of PKA. PKA can go on to inhibit PP1, thus inhibiting the dephosphorylation pathway, and providing some explanation for how LTP and LTD can run in parallel without running in conflict. Calcineurin has a much greater affinity for Ca²⁺ than CaMKII, and thus is activated at much lower [Ca²⁺]. Thus, we see that when [Ca²⁺] is high, the PKA and CaMKII pathway dominates, whilst when [Ca²⁺] is low, the calcineurin and PP1 pathway dominates.

 

As seen in the BCM model, there exists a _m in the middle of the range where there is no long-term change in synaptic plasticity. Experiments by Aggleton et al, (2001), have focussed on this transition point between LTP and LTD where no plasticity is seen, trying to determine whether it occurs as a result of the induction of both LTP and LTD simultaneously (and thus no net change), or whether neither LTP nor LTD is being induced at this point. They carried out a pairing protocol (low-frequency simtulation to neurons held at between -70 to -40mV for LTD induction, or -10mV for LTP induction) in the rat perirhinal cortex in vitro whilst using EGTA to buffer the activity dependent increase in [Ca²⁺]. They used the protein kinase inhibitor staurosporine so selectively block LTP (it doesn’t block LTD), and the mGluR antagonist MCPG to selectively block LTD (it doesn’t block LTP). They were able to show that at the point of transition, blocking LTP did not uncover LTD and vice versa. This suggests that the transition is due to a lack of induction of both and that the two processes are induced independently of each other. Furthermore, MCPG application during LTP induction did not enhance the magnitude of LTP induced, and staurosporine application did not uncover LTD. Thus provides further evidence that the processes are independent, and that there is an inactivation of LTD at Ca²⁺ levels that induce LTP (in agreement with the idea that cAMP could act to inhibit LTD induction).

 

In conclusion, we see that NMDAR-dependent Ca²⁺ influx in the postsynaptic cell is crucial for the induction of both LTP and LTD. Importantly, the difference in the kinetics and magnitude of the Ca²⁺ signal evoked in the postsynaptic neuron is critical in initiating markedly different biochemical cascades. Indeed, LTP and LTD are brought about through different mechanisms and they occur independently of each other.

Filed Under: Neuroscience LTP LTD