The plasticity of neural plasticity

Metaplasticity is the modulation by experience of neuronal plasticity. It is a family of adaptive processes that have probably evolved to form a dynamic balance among the need for change (*plasticity), the need to resist too much change (*homeostasis, *memory, *persistence), and the metabolic price of both, at various periods in the life of the organism (*development). Metaplasticity is commonly referred to as the plasticity of *synaptic plasticity (Abraham and Bear 1996; Abraham and Tate, 1997), but there is good reason to believe that the underlying mechanisms involve the neuronal cell body as well. The concept of metaplasticity fits to be used in the discussion of higher *levels of organization as well. For example, it is legitimate to say that the language areas of the brain undergo metaplastic changes with age. It is, however, assumed that metaplastic changes that are manifested at the circuit or *system level, are the consequence of metaplasticity at the synaptic level.

Most research on metaplasticity concerns activity that primes the expression of subsequently induced *long-term potentiation (LTP) or of long-term depression (LTD). Part of this work is conducted on *hippocampal preparations (e.g. Huang et al. 1992; Christie and Abraham 1992), and part on *cortical preparations with special emphasis on developmental plasticity in the visual cortex (Kirkwood et al. 1996). In these systems, under appropriate conditions, prior activity can be shown to regulate the capacity to undergo LTP and LTD (Abraham and Tate 1997).

An influential theoretical framework for meta-plasticity in the mammalian brain was proposed by Bienenstock, Cooper, and Monro (known in the field as the BCM *model; Bienenstock et al. 1982). This model was developed to account for the developmental plasticity of *stimulus selectivity in the mammalian sensory cortex. The model makes two basic assumptions. One, that synaptic modification varies as a nonlinear function of postsynaptic activity, such that low levels of afferent activity result in LTD whereas high levels in LTP. The crossover from LTD to LTP occurs at the modification threshold 9m. The second assumption of the model is that 9m slides as a function of synaptic history, hence endowing the system with metaplasticity. This sliding threshold keeps the active synapse within a dynamic range, preventing saturation of LTP on the one hand and complete depression by LTD on the other (ibid.). Some experimental data echo the assumptions of the BCM model. For example, Kirkwood et al. (1996) found that in the developing cortex, 0m indeed depends on sensory experience (Figure 47): in the visual cortex of light-deprived rats, LTP is enhanced and LTD diminished over a range of stimulation frequencies, but the effect is reversed by brief light exposure. This shift may contribute to the experience-dependent modifications of visual receptive fields in

Fig. 47 Experience-dependent metaplasticity in the 'developing visual system. Kirkwood et al. (1996) have measured the change in synaptic responses in slices prepared from the visual *cortex of light-deprived (closed circles) and 'control (open circles) 4-6-week-old rats. The measurement was done at 20-30 min after the stimulation. The per cent change in synaptic response is depicted as a function of the stimulation frequency. It can be seen that visual experience shifts the long-term depression (LTD, negative change)—long-term potentiation (*LTP, positive change) cross-over point (termed 8m in the BCM *model,see text). (Adapted from Kirkwood et al. 1996.)

0.1 1 10 100 Stimulation frequency

Fig. 47 Experience-dependent metaplasticity in the 'developing visual system. Kirkwood et al. (1996) have measured the change in synaptic responses in slices prepared from the visual *cortex of light-deprived (closed circles) and 'control (open circles) 4-6-week-old rats. The measurement was done at 20-30 min after the stimulation. The per cent change in synaptic response is depicted as a function of the stimulation frequency. It can be seen that visual experience shifts the long-term depression (LTD, negative change)—long-term potentiation (*LTP, positive change) cross-over point (termed 8m in the BCM *model,see text). (Adapted from Kirkwood et al. 1996.)

the cortex following manipulation of visual experience (*development).

Multiple molecular and cellular mechanisms may account for metaplasticity over a spectrum of developmental stages, brain regions, synaptic specificities, and time courses. The experience-dependent release of growth factors and neuromodulators probably primes circuits to respond differentially to subsequent plasticity-inducing stimuli (e.g. Markram and Segal 1990; Kaneko et al. 1997; Abraham and Tate 1997). At their cellular targets, these stimuli modulate receptors, *intracellular signalling cascades, and their downstream substrates. It has been particularly proposed that variations in the *calcium-independent activity of the enzyme calcium-calmodulin dependent *protein kinase type II (CaMKII), shifts 0m in the hippocampus (Mayford et al. 1995; see also commentary in Deisseroth et al. 1995). Another type of candidate mechanism for metaplastic-ity is local tagging and local *protein synthesis in synapses; during the synaptic *consolidation time window, the recent history of the neuron could determine whether a stimulus will be encoded in long-term memory or, alternatively, forgotten (Frey and Morris 1997).

Metaplasticity was also explored in an invertebrate, *Aplysia. The advantage of studying this system lies in the ability to relate events at the cellular, circuit, and behavioural level, respectively. The circuits that encode the defensive withdrawal reflexes in Aplysia are composed of a number of cell types, including sensory neurons that receive the tactile information from the skin, motor neurons that execute the withdrawal reflex, and interneurons that feed into the sensory and motor neurons information from various parts of the organism (Figure 5, p. 16). In the circuit that mediates the siphon withdrawal reflex, the L29 excitatory interneurons synapse on to the motor neurons, whereas the L30 inhibitory interneurons synapse on to L29. By inhibiting L29, activation of L30 suppresses the ability of siphon stimulation to elicit the reflex. L30 receives input from the excitatory interneurons that relay tactile information from the siphon skin; this forms a negative feedback loop, which limits the activation of the reflex. Activation of L30 can induce multiple types of plasticity. One type, frequency facilitation (FF), involves a steady increase in the strength of the synaptic connection during the burst of nerve impulses. Another type of plasticity, short-term enhancement (STE), involves augmentation of response that outlasts the stimulus by about 1 min. The most important findings in the context of this discussion is that L30 is also influenced by tactile information from the tail. If a weak tactile stimulus is applied to the tail shortly before a tactile stimulus is applied to the siphon, the inhibition of L30 by siphon stimulation is enhanced. If instead the tail is shocked (or the "neurotransmitter serotonin is applied in an imitation experiment, "method), the capacity for STE in the L30-L29 inhibitory synapse is suppressed, while leaving the capacity for FF intact (Fischer et al. 1997). In other words, the tail shock selectively modulates the ability of the synapse to undergo short-term use-dependent plasticity, i.e. it induces metaplasticity. Similarly, in the behaving animal, tail shock suppresses the inhibitory modulation of the siphon withdrawal reflex after tactile stimulation of the tail. This phenomenon was termed 'modulatory metaplasticity', because its induction does not require activity of the synapse whose plasticity is being regulated, as tail shock itself does not activate L30 (ibid.).

A valuable take-home message from the metaplasticity studies relates to the importance of the history of the experimental "subject or preparation and to the influence of this history on the outcome of the experiment. The investigation of metaplasticity reminds us that individual subjects or preparations, even if "controlled for age, gender, "nutrition, or "context at the time of experiment, etc., could still differ not only in terms of their particular past experience on a specific activity or item of information, but also in their activity dependent "capacity to undergo plastic changes at any particular moment in time.

Selected associations: Development, Homeostasis, Long-term potentiation, Plasticity

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