Parvalbumin-expressing basket-cell network plasticity induced by experience regulates adult learning

Abstract

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.

Hippocampal Neural Disinhibition Causes Attentional and Memory Deficits

“…Our finding, highlighting the importance of GABAergic inhibition for hippocampusdependent memory performance, converges with recent studies in mice reporting learning-related increase of hippocampal inhibitory synapses (Ruediger et al 2012) and impaired memory performance following disruption of hippocampal GABA neuron function by molecular-, opto-or pharmacogenetic approaches (Prut et al 2010;Murray et al 2011;Andrews-Zwilling et al 2012;Caputi et al 2012;Donato et al 2013;Gilani et al 2014;Lovett-Barron et al 2014;Engin et al 2015;Lee et al 2016). Moreover, our findings support recent studies in humans and rodent models linking hippocampal overactivity and hyperexcitability to age-related memory deficits (Koh et al 2010;Bakker et al 2012;Davis et al 2014) and are consistent with the correlation of hippocampal overactivity with memory deficits in schizophrenia (Tregellas et al 2014).…”

“…Moreover, our findings support recent studies in humans and rodent models linking hippocampal overactivity and hyperexcitability to age-related memory deficits (Koh et al 2010;Bakker et al 2012;Davis et al 2014) and are consistent with the correlation of hippocampal overactivity with memory deficits in schizophrenia (Tregellas et al 2014). However, hippocampal neural disinhibition may facilitate hippocampal synaptic plasticity and, thereby, improve memory, if such disinhibition is finely and dynamically regulated by endogenous plasticity (Donato et al 2013) or if there is a pre-existing deficit due to increased neural inhibition (Fernandez et al 2007). …”

Assessment and modulation of cortical inhibition using transcranial magnetic stimulation

“…2). Similar correlations between PV expression and the balance of excitatory and inhibitory synaptic inputs were earlier described in the hippocampus of mice (Donato et al, 2013). Another electrophysiological study in the primary somatosensory cortex of rats further demonstrates that a decrease of PV expression, induced by iTBSrTMS, is accompanied by an increase of sensory responses (Thimm and Funke, 2015).…”

Activity-dependent inhibitory synapse remodeling through gephyrin phosphorylation

“…Our data identify a mechanism through which neuronal activity can exert a homeostatic control of the number and function of perisomatic inhibitory synapses. This phenomenon may be critically important to individually optimize the level of inhibition on pyramidal neurons and, thus, set the proper balance required for the synchronization of oscillations mediated by parvalbumin interneurons during learning (29,33,34).…”