PP1/PP2A phosphatase inhibition-induced metaplasticity in protein synthesis blocker-treated hippocampal slices: LTP and LTD, or There and Back again

The hippocampus has a pivotal role in learning and in the formation and consolidation of memory and is critically involved in the regulation of emotion, fear, anxiety, and stress. Studies of the hippocampus have been central to the study of memory in humans and in recent years, the regional specialization and organization of hippocampal functions have been elucidated in experimental models and in human neurological and psychiatric diseases. The hippocampus has long been considered a classic model for the study of neuroplasticity as many examples of synaptic plasticity such as long-term potentiation and -depression have been identified and demonstrated in hippocampal circuits. Neuroplasticity is the ability to adapt and reorganize the structure or function to internal or external stimuli and occurs at the cellular, population, network or behavioral level and is reflected in the cytological and network architecture as well as in intrinsic properties of hippocampal neurons and circuits. The high degree of hippocampal neuroplasticity might, however, be also negatively reflected in the pronounced vulnerability of the hippocampus to deleterious conditions such as ischemia, epilepsy, chronic stress, neurodegeneration and aging targeting hippocampal structure and function and leading to cognitive deficits. Considering this framework of plasticity and vulnerability, we here review basic principles of hippocampal anatomy and neuroplasticity on various levels as well as recent findings regarding the functional organization of the hippocampus in light of the regional vulnerability in Alzheimer's disease, ischemia, epilepsy, neuroinflammation and aging.

Long-term potentiation (LTP) with its extremely long duration has been frequently regarded as an elementary mechanism of information storage in the nervous system or at least as a suitable model for the study of mechanisms underlying functional plasticity and processes of learning and memory formation. Considering the necessity of an increased protein synthesis for memory consolidation and for the maintenance of LTP in granular synapses in vivo it was of interest to determine whether the LTP of the CA1 region of the hippocampus depends on protein synthesis as well. For the solution of this question anisomycin (ANI), a reversible blocker of protein synthesis, was used at a concentration of 20 microM, which blocked the [3H]leucine incorporation in hippocampal slices by at least 85%. It has been shown that in the CA1 region in vitro the maintenance of LTP (i.e. a late phase greater than 5 h) depends on an ongoing protein synthesis. A 3-h treatment with ANI immediately following multiple tetanization resulted in gradually developing loss of field excitatory postsynaptic potential (EPSP) and population spike (PS) potentiation (15 +/- 19% increase of the PS instead of the 96 +/- 14% increase in non-treated control experiments at the 8th h after tetanization). Furthermore, a late PS potentiation (greater than 6 h) of a second non-tetanized pathway to CA1 pyramidal cells has been observed (increase by 64 +/- 18% at the 8th h) for the first time. This potentiation was ANI-sensitive as well and suggests that the maintenance of LTP is dependent on a postsynaptic mechanism.

Long-term potentiation (LTP) is generally divided into two phases, early (E-) and late (L-) LTP, of which only L-LTP is thought to depend on protein synthesis. Here we report that E-LTP can also be dependent on protein synthesis at higher levels of synaptic activation. Moreover, we show that the requirement for protein synthesis during L-LTP extends beyond the early induction phase and that it depends on synaptic stimulation. This suggests that the level of neuronal activity is a crucial determinant for the role of protein synthesis in E- and L-LTP.