Long-term memory of complex olfactory learning is expressed by wide spread enhancement in excitatory and inhibitory synaptic transmission onto piriform cortex pyramidal neurons. A particularly interesting modification in synaptic inhibition is the hyperpolarization of the reversal potential of the fast post synaptic inhibitory potential (fipSp). Here we study the mechanism underlying the maintenance of such a shift in the fIPSP. Blocking of the neuronal specific K +-cl − co-transporter (KCC2) in neurons of trained rats significantly depolarized the averaged fIPSP reversal potential of the spontaneous miniature inhibitory post synaptic currents (mIPSCs), to the averaged pre-training level. A similar effect was obtained by blocking PKC, which was previously shown to upregulate KCC2. Accordingly, the level of PKC-dependent phosphorylation of KCC2, at the serine 940 site, was significantly increased after learning. In contrast, blocking two other key second messenger systems CaMKII and PKA, which have no phosphorylation sites on KCC2, had no effect on the fIPSP reversal potential. Importantly, the PKC inhibitor also reduced the averaged amplitude of the spontaneous miniature excitatory synaptic currents (mepScs) in neurons of trained rats only, to the pre-training level. We conclude that learning-induced hyper-polarization of the fIPSP reversal potential is mediated by PKC-dependent increase of KCC2 phosphorylation. The notion that synaptic inhibition has a central role in memory formation and maintenance has been gaining strong support by recent studies 1-6. Learning-induced modulation of inhibitory synaptic transmission was shown in several brain areas, following different training paradigms 2,7-11. It has been suggested that long-lasting enhancement in synaptic inhibition is required to allow long-term memory maintenance while preventing uncontrolled hyper-excitability 5,12-14. The mechanisms underlying learning-induced and activity-induced plasticity of synaptic inhibition have been the subject of an increasing number of studies 9,15-17. We previously showed that complex olfactory-discrimination (OD) learning results in a long-lasting enhancement of GABA A-mediated inhibitory synaptic transmission in piriform cortex pyramidal neurons, which is widely spread throughout the piriform cortex pyramidal cell population 9,11,13,14,16,18. Such learning-induced enhanced inhibition is mediated by two mechanisms; increased single-channel conductance of the GABA A-channel receptor 11,13 and a hyperpolarizing shift in the chloride current mediated fIPSP reversal potential, 9,18. Learning-induced enhancement of the GABA A channel conductance is maintained for days by persistent CaMKII activation 11. The molecular mechanism that enables long-lasting hyperpolarization of the fIPSP reversal potential is yet to be explored. The chloride reversal potential is determined to a great extent by the combined action of two co-transporters; the Na +-K + , 2Cl − co-transporter (NKCC1) increases intracellular Cl − concentration, thus depola...
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Memory of an ordered sequence of distinct events requires encoding the temporal order as well as the intervals that separates these events. In this study, using order place association task where the animal learns to associate the location of the food pellet to the order of entry into the event arena, we probe the nature of temporal order memory in mice. In our task, individual trials, become distinct events, as the animal is trained to form unique association between entry order and a correct location. The inter-trial intervals (> 30 mins) are chosen deliberately to minimise the working memory contributions. We develop this paradigm initially using 4 order place associates and later extend it to 5 paired associates. Our results show that animals not only acquire these explicit (entry order to place) associations but also higher order associations that can only be inferred implicitly from the temporal order of these events. As an indicator of such higher order learning during the probe trail the mice exhibit predominantly prospective errors that declines proportionally with temporal distance. On the other hand, prior to acquiring the sequence the retrospective errors are dominant. Additionally, we also tested the nature of such acquisitions when temporal order CS is presented along with flavour as a compound stimulus comprising of order and flavour both simultaneously being paired with location.Results from these experiments indicate that the animal learns both order-place and flavourplace associations. Comparing with pure order place training, we find that the additional flavour in compound training did not interfere with the ability of the animals to acquire the order place associations. When tested remotely, pure order place associations could be retrieved only after a reminder training. Further higher order associations representing the temporal relationship between the events is markedly absent in the remote time..
Memory of an ordered sequence of distinct events requires encoding the temporal order as well as the intervals that separates these events. In this study, using order place association task where the animal learns to associate the location of the food pellet to the order of entry into the event arena, we probe the nature of temporal order memory in mice. In our task, individual trials, become distinct events, as the animal is trained to form unique association between entry order and a correct location. The inter-trial intervals (> 30 mins) are chosen deliberately to minimise the working memory contributions. We develop this paradigm initially using 4 order place associates and later extend it to 5 paired associates. Our results show that animals not only acquire these explicit (entry order to place) associations but also higher order associations that can only be inferred implicitly from the temporal order of these events. As an indicator of such higher order learning during the probe trail the mice exhibit predominantly prospective errors that declines proportionally with temporal distance. On the other hand, prior to acquiring the sequence the retrospective errors are dominant. Additionally, we also tested the nature of such acquisitions when temporal order CS is presented along with flavour as a compound stimulus comprising of order and flavour both simultaneously being paired with location. Results from these experiments indicate that the animal learns both order-place and flavour-place associations. Comparing with pure order place training, we find that the additional flavour in compound training did not interfere with the ability of the animals to acquire the order place associations. When tested remotely, pure order place associations could be retrieved only after a reminder training. Further higher order associations representing the temporal relationship between the events is markedly absent in the remote time.
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