Intra-spaced stimulation and protein phosphatase 1 dictate the direction of synaptic plasticity

Abstract

Changes in the strength of synapses in the hippocampus that occur with long-term potentiation (LTP) or long-term depression (LTD) are thought to underlie the cellular basis of learning and memory. Memory formation is known to be regulated by spacing intervals between training episodes. Using paired whole-cell recordings to record from synapses connecting two CA3 pyramidal neurons, we now show that stimulation frequency and spacing between LTP and LTD induction protocols alter the expression of synaptic plasticity. These effects were found to be dependent on protein phosphatase 1 (PP1), an essential protein serine/threonine phosphatase involved in synaptic plasticity, learning and memory. We also show for the first time that PP1 not only regulates the expression of synaptic plasticity, but also has the ability to depress synaptic transmission at basal activity levels. Moreover, PP1 can sort two consecutive messages received by the postsynaptic neuron and control the direction of change in synaptic strength. This study highlights new roles of PP1 in regulating timing-dependent constraints on the expression of synaptic plasticity that may correlate with memory processes, and together PP1 and the spacing of stimulation protocols provide mechanisms to regulate the expression of synaptic plasticity at CNS synapses.

Bidirectional regulation of synaptic plasticity in the basolateral amygdala induced by the D1‐like family of dopamine receptors and group II metabotropic glutamate receptors

“…; Genoux et al . ). Hence, we reasoned that if prior activation of D 1 Rs could attenuate LY‐SD by activating an AC signalling pathway in glutamatergic terminals, then the kinetics of inactivation of the AC‐PKA signalling cascade may also play a pivotal role in regulating the efficacy of mGluR 2/3 to induce depotentiation of previously enhanced synaptic plasticity.…”

“…Many neuronal models of memory storage include bidirectional modifications of synaptic strength, namely synaptic potentiation and depression (Sejnowski, ), both of which are thought to be necessary for error correcting (Willshaw & Dayan, ; Hancock et al ., ). Consistent with this hypothesis, genetic distuption of sub‐synaptic proteins, which attenuate hippocampal LTD and facilitate LTP, has been shown to impair spatial learning and memory (Migaud et al .…”

Paired Whole Cell Recordings in Organotypic Hippocampal Slices

“…Using this technique has allowed the predictions of pre-and postsynaptic models of synaptic plasticity to be directly tested. In addition, the phenotype of silent synapses, and specific roles of active-zone and PSD proteins have also been described in this preparation [6][7][8][9][10][11][12][13][14][15][16] . It has also enabled the discovery that synapses exist in distinct electrophysiologically-defined states, and that during synaptic plasticity synapses move between these states 9,17 .…”

“…The use of organotypic brain slice cultures circumvents this obstacle as synaptic connectivity can re-establish in vitro and moreover the nature of the resulting connectivity is similar to that in native brain tissue 20 . In addition, organotypic cultures express LTP, LTD [7][8][9][10][12][13][14][15]21 and additional forms of short-term synaptic plasticity including pairedpulse facilitation (PPF) and depression (PPD) 6,22,23 , enabling plasticity mechanisms to be studied in pairs of neurons. Here we describe the detailed methodology involved in successfully attaining paired recordings in this in vitro system.…”

“…Over the past fifteen years we have routinely used paired whole-cell recordings from two synaptically connected pyramidal neurons [6][7][8][9][10][11][12][13][14][15][16][17] .…”