Multiple forms of metaplasticity at a single hippocampal synapse during late postnatal development

Abstract

Metaplasticity refers to adjustment in the requirements for induction of synaptic plasticity based on the prior history of activity. Numerous forms of developmental metaplasticity are observed at Schaffer collateral synapses in the rat hippocampus at the end of the third postnatal week. Emergence of spatial learning and memory at this developmental stage suggests possible involvement of metaplasticity in the final maturation of the hippocampus. Three distinct metaplastic phenomena are apparent. (1) As transmitter release probability increases with increasing age, presynaptic potentiation is reduced. (2) Alterations in the composition and channel conductance properties of AMPARs facilitate the induction of postsynaptic potentiation with increasing age. (3) Low frequency stimulation inhibits subsequent induction of potentiation in animals older but not younger than 3 weeks of age. Thus, many forms of plasticity expressed at SC-CA1 synapses are different in rats younger and older than 3 weeks of age, illustrating the complex orchestration of physiological modifications that underlie the maturation of hippocampal excitatory synaptic transmission. This review paper describes three late postnatal modifications to synaptic plasticity induction in the hippocampus and attempts to relate these metaplastic changes to developmental alterations in hippocampal network activity and the maturation of contextual learning.

Keywords: Hippocampus; Long-term depression; Long-term potentiation; Metaplasticity; Postnatal development; Schaffer collateral.

Fig. 1

Illustration of the basic difference between synaptic plasticity and metaplasticity. (A) In a naïve sample (Sample 1), a plasticity-inducing stimulus results in potentiation of the synaptic response. (B) During Sample 2, following a metaplastic event, the same plasticity-inducing stimulus no longer alters synaptic efficacy. Green bars depict the difference in the amplitude of the evoked synaptic event before and after the plasticity-inducing stimulus. This example does not reflect all types of metaplasticity.

Fig. 2

Summary of pertinent developmental events in the hippocampus. Age related changes in LTP, transmitter release probability, and postsynaptic glutamate receptors are shown in relation to eyelid parting, spatial exploration, and spatial learning. Brackets denote relationships between alterations in synaptic plasticity and baseline transmission.

Fig. 3

Presynaptic LTP is reduced in concert with the developmental increase in baseline transmitter release probability. (A) At 15 days of age, transmitter release probability is low, as reflected by large magnitude paired-pulse facilitation (PPF). Subsequently, LTP magnitude is large and there is a reduction in PPF during LTP expression. (B) At 30 days of age, transmitter release probability is increased, as reflected by an increase in the baseline EPSP amplitude and reduced PPF compared to 15 days of age. At this developmental stage, the same plasticity-inducing stimulus (5 × 200 Hz) does not elicit presynaptic LTP. (C) The increased induction threshold for presynaptic LTP at 30 days of age can be overcome with a stronger plasticity-inducing stimulus (10 × 200 Hz). Red bars depict the difference in amplitude of the evoked response across paired stimulus pulses (50 ms inter-pulse interval). Green bars depict the difference in the amplitude of the evoked synaptic event before and after the plasticity-inducing stimulus.

Fig. 4

Alterations in AMPAR number and composition at SC-CA1 synapses across postnatal development. The number of AMPARs increases across the first three postnatal weeks through insertion of AMPARs containing GluA1 (left to middle transition). The increase in AMPAR number results in an increase in synaptic efficacy (bottom waveforms). AMPARs containing GluA1 are replaced by AMPARs with GluA3 such that, by the end of the third postnatal week, more AMPARs contain GluA3 than GluA1 (middle to right transition). This change in AMPAR composition prolongs AMPAR-mediated synaptic responses (bottom waveforms). The increased duration of AMPAR-mediated synaptic responses at 3 weeks of age reduces the threshold for LTP induction. Green bars depict the difference in the amplitude of the evoked synaptic event as more AMPARs are inserted into maturing synapses.

Fig. 5

Experimental theta stimulation protocols and illustrations of endogenous theta oscillations in an immature and mature hippocampal network. (A) Artificial stimulus protocols have been shown to robustly induce LTP in adult hippocampal slices. At left is the stimulus pattern for primed-burst potentiation (PBP). At right is the stimulus pattern for theta-burst potentiation (TBP). (B) An illustration of a filtered EEG trace recorded in area CA1 of the hippocampus at 15 days of age. Action potentials (APs) from a single neuron are superimposed. Theta power is reduced relative to more mature animals and CA1 pyramidal neurons do not burst. The result is an increased proclivity to induce LTD during bouts of theta (Kleshchevnikov, 1999). (C) An illustration of a filtered EEG trace recorded in area CA1 of the hippocampus at 30 days of age. Theta power is increased relative to less mature animals and CA1 pyramidal neurons burst in relation to the theta rhythm. The result is an increased proclivity to induce LTP during bouts of theta activity.

Fig. 6

Relationships between the type of LTP expressed (non-associative versus associative) and patterns of synaptic strengthening in sparsely connected immature and mature CA3–CA1 neuronal networks. (A) Non-associative LTP induction is dependent solely on the activity state of the presynaptic neuron. Reduction in the constraints for LTP induction results in more synapses undergoing LTP. (B) Associative LTP induction is restricted to synapses with coincident pre- and post-synaptic activity.

Fig. 7

Associative synaptic plasticity permits overlap in the neural ensembles that represent adjacent locations in a testing environment. (A) The line on the parallelogram depicts the path of a rat moving across a testing platform. Numbers indicate timepoints when the ensembles below become activated. (B) Small samples of CA1 place cells at the timepoints marked in panel A. At 15 days of age, a preponderance of non-associative synaptic plasticity mechanisms results in minimal overlap in the ensembles that represent adjacent locations on the testing platform. At 23 days of age, waning of non-associative plasticity mechanisms unmasks synaptic alterations due to associative plasticity. The result is an increase in the overlap of ensembles that represent adjacent locations on the testing platform. Red ovals are neurons that are active in two adjacent locations on the platform. Green ovals represent neurons that were active in one position, but not in an adjacent position. Associative synaptic plasticity permits sequential activation of ensembles that depict the past trajectory or future path of the animal.