P.1.013 - Optical and pharmacological activation of TrkB receptors in parvalbumin interneurons induces plasticity in the adult visual cortex

Abstract

Brain network plasticity occurs principally during critical periods in early postnatal life [1]. Chronic treatment with the antidepressant fluoxetine, however, can induce critical period-like plasticity (iPlasticity), such as shift of ocular dominance after monocular deprivation [2]. Fluoxetine activates the neurotrophic BDNF/TrkB pathway and is thought to be a crucial modulator of iPlasticity [3]. We aim to identify the mechanisms of iPlasticity and the neuronal subpopulations expressing TrkB that are responsible for the profound events observed in that process. Especially, Parvalbumin-positive GABAergic interneurons play a major role in regulating synaptic plasticity in the visual cortex [2]. TrkB receptors are highly enriched in Parvalbumin interneurons [4] and closure of critical periods is promoted by maturation of the intracortical Parvalbumin GABAergic network inhibiting critical period and ocular dominance plasticity. It is widely accepted that visual cortex plasticity requires a reduction in Parvalbumin GABAergic interneuron-mediated inhibition resulting in the activation of a large population of pyramidal neurons and subsequent synchronization of the brain network [1]. Given the importance of Parvalbumin in regulating plasticity events, we hypothesize that fluoxetine-induced plasticity in the adult visual cortex is mediated through TrkB receptors expressed in Parvalbumin GABAergic interneurons. We used the validated shift of ocular dominance paradigm as previously described [5] to study visual cortex plasticity, analyzed the data with two-way ANOVA and demonstrate that Parvalbumin GABAergic interneurons are key regulators in ocular dominance plasticity. Using an inhibition approach, we show that in heterozygous Parvalbumin-specific TrkB knockout mice (hPV-TrkB cKO) the fluoxetine-induced shift in ocular dominance is absent (p = 0.6185) while wild-type mice show a robust shift induced by chronic fluoxetine treatment (p = 0.0002). Also, we have developed DIO-optoTrkB, a double-inverted open reading frame lentivirus construct that is dependent on cre-recombinase, for cell type-specific expression in vivo and optogenetic stimulation promotes the dimerization and autophosphorylation of optoTrkB in Parvalbumin interneurons. During the shift in ocular dominance paradigm, specific optogenetic activation of optoTrkB induces the shift in ocular dominance in a stimulation-dependent manner when combined with monocular deprivation of the stronger eye (p 0.03). These data show a strikingly new and opposing role of intracortical inhibition by Parvalbumin GABAergic interneurons in ocular dominance and induction of iPlasticity, offering a new idea about the underlying mechanisms of plasticity during the critical period and adulthood. We propose a new tool to investigate neuropsychological disorders, such as amblyopia and post-traumatic stress disorder, by optically controlling neuronal plasticity in a neuron-specific manner.