Mechanisms of Neuroadaptation and the Regulation of Cognition

Perirhinal cortex plays a key role in processing recognition memory. Evidences that repeated exposure to familiar objects produces a decremental response in perirhinal neurones led to the proposal that recognition memory depends on long-term depression. However, long-term potentiation is also expressed in perirhinal cortex. Long-term potentiation is thought to be involved in many form of synaptic plasticity, especially learning and memory. Nevertheless, not much is known on mechanisms maintaining late-phases of long-term depression in perirhinal cortex. This study shows that LTP in adult perirhinal cortex is maintained by the persistent activity of Protein Kinase Mζ. The inhibition of PKMζ, in fact, completely reverts an established potentiation. This work also focuses on mechanisms that could regulate the persistent activation of PKMζ in perirhinal cortex. The results of the experiments show that synaptic depotentiation appear to down-regulate the activity of PKMζ. Also, the role of PDK1 in regulating the activity of PKMζ is studied. The experiments run provide evidences that the inhibition of PDK1 leads to a decrease of the activity of PKMζ. This work also explores the mechanisms of synaptic plasticity occurring in perirhinal cortex early in the development. Starting from the observation that it’s not possible to induce LTP in P14 animals, and the only form of potentiation obtainable in P14 perirhinal cortex is de-depression, several experiments have been run to investigate the possible mechanisms underlying this “high levels” of basal synaptic transmission at this stage. PKMζ maintains long-term synaptic potentiation; in P14 perirhinal cortex, the application of the selective PKMζ inhibitor ZIP decreases basal synaptic transmission, but has no effect once LTD has been induced. Moreover, ZIP decreases synaptic transmission in a previously de-depressed pathway, 4 providing evidences that in P14 perirhinal cortex LTP mechanisms are present but already saturated in a PKMζ-dependent way. This potentiation of the basal synaptic transmission is lost later during the neurodevelopment (i.e. at PND35); at this stage it is possible to induce LTP in perirhinal cortex, and the inhibition of PKMζ completely reverts the potentiation. Mechanisms regulating the sustained activity of PKMζ in P14 perirhinal cortex are also examined in this work. New PKMζ is synthesized following the induction of LTP via intracellular mechanisms involving different kinases (i.e. PI3K) and ultimately mTOR-dependent translation. The inhibition of PI3K and mTOR in P14 perirhinal cortex produces a PKMζ-dependent decrease in the basal synaptic response. Therefore, our results suggest that synaptic transmission in immature connections in perirhinal cortex relies on PI3K-, mTOR- and PKMζ-dependent mechanisms. Further experiments show that these processes could be regulated by a continuous activity of Group I mGluRs. Taken together, these results highlight the crucial role of PKMζ in the synaptic potentiation, and suggest that its sustained activity is required to stabilize young synapses during the neurodevelopment.