Scientific Understanding of Consciousness
Plasticity of Basket-Cell Network Regulates Adult Learning
Nature 504, 272–276 (12 December 2013)
Parvalbumin-expressing basket-cell network plasticity induced by experience regulates adult learning
Flavio Donato, Santiago Belluco Rompani & Pico Caroni
Friedrich Miescher Institut, Maulbeerstrasse 66, CH-4058 Basel, Switzerland
Learning and memory processes can be influenced by recent experience, but the mechanisms involved are poorly understood. Enhanced plasticity during critical periods of early life is linked to differentiating parvalbumin (PV)-interneuron networks, suggesting that recent experience may modulate learning by targeting the differentiation state of PV neurons in the adult. Here we show that environmental enrichment and Pavlovian contextual fear conditioning induce opposite, sustained and reversible hippocampal PV-network configurations in adult mice. Specifically, enrichment promotes the emergence of large fractions of low-differentiation (low PV and GAD67 expression) basket cells with low excitatory-to-inhibitory synaptic-density ratios, whereas fear conditioning leads to large fractions of high-differentiation (high PV and GAD67 expression) basket cells with high excitatory-to-inhibitory synaptic-density ratios. Pharmacogenetic inhibition or activation of PV neurons was sufficient to induce such opposite low-PV-network or high-PV-network configurations, respectively. The low-PV-network configuration enhanced structural synaptic plasticity, and memory consolidation and retrieval, whereas these were reduced by the high-PV-network configuration. We then show that maze navigation learning induces a hippocampal low-PV-network configuration paralleled by enhanced memory and structural synaptic plasticity throughout training, followed by a shift to a high-PV-network configuration after learning completion. The shift to a low-PV-network configuration specifically involved increased vasoactive intestinal polypeptide (VIP)-positive GABAergic boutons and synaptic transmission onto PV neurons. Closely comparable low- and high-PV-network configurations involving VIP boutons were specifically induced in primary motor cortex upon rotarod motor learning. These results uncover a network plasticity mechanism induced after learning through VIP–PV microcircuit modulation, and involving large, sustained and reversible shifts in the configuration of PV basket-cell networks in the adult. This novel form of experience-related plasticity in the adult modulates memory consolidation, retrieval and learning, and might be harnessed for therapeutic strategies to promote cognitive enhancement and neuroprotection.
To determine whether plasticity and learning in the adult may involve alterations in the differentiation state of PV-positive GABA (γ-aminobutyric acid)-ergic interneurons, we monitored PV immunoreactivity in ensembles of genetically identified PV neurons near the pyramidal cell layer in dorsal hippocampal area CA3b. We initially compared cage control to environmentally enriched, and to contextually fear conditioned mice. The environmental enrichment protocol enhances hippocampal plasticity and learning, whereas fear specifically restricted to training context depends on enhanced filopodial synapses onto PV neurons by hippocampal mossy fibres upon contextual fear conditioning.
To investigate how defined subpopulations of PV neurons are influenced by experience, we analysed presynaptic terminals of basket and chandelier cells, the two main subpopulations of hippocampal PV neurons in CA3. PV immunoreactivity signals were comparable at soma, axonal boutons and dendrites of individual PV basket cells.
Our results reveal a specific circuit mechanism through which recent experience modulates plasticity, memory consolidation and retrieval, and learning in the adult. We provide evidence that PV basket cells, whose differentiation regulates critical period plasticity, exhibit pronounced differentiation plasticity in the adult, and that this involves major structural alterations in excitatory and inhibitory synaptic puncta densities onto PV neurons. These alterations might facilitate excitatory recruitment of high-PV- and high-GAD67-expressing basket cells and reduce excitatory recruitment of low-PV and low-GAD67-expressing basket cells. The shift to a low-PV-network configuration might facilitate the combination, consolidation and retrieval of associations established by comparatively weak synaptic networks during incremental trial-and-error learning, whereas the shift to a high-PV-network configuration might promote the establishment of strong memories by comparatively strong synaptic networks and prevent establishment and retrieval of distractor memories. In addition, shifts to low-PV-network configurations might prevent premature establishment of dominant memories, whereas high-PV-network shifts might strengthen appropriate memories and enhance feedforward entrainment upon skill learning due to enhanced gamma coherence. Reductions in PV and GAD67 levels have been consistently detected in patients with schizophrenia, suggesting that dysfunction of excitation–inhibition microcircuits involving PV-network regulation may underlie cognitive disruption in this devastating psychiatric condition.
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