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Abstract
Elevated states of brain plasticity typical for critical periods of early postnatal life can be reinstated in the adult brain through interventions, such as antidepressant treatment and environmental enrichment, and induced plasticity may be critical for the antidepressant action. Parvalbumin-positive (PV) interneurons regulate the closure of developmental critical periods and can alternate between high and low plasticity states in response to experience in adulthood. We now show that PV plasticity states and cortical networks are regulated through the activation of TrkB neurotrophin receptors. Visual cortical plasticity induced by fluoxetine, a widely prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant, was lost in mice with reduced expression of TrkB in PV interneurons. Conversely, optogenetic gain-of-function studies revealed that activation of an optically activatable TrkB (optoTrkB) specifically in PV interneurons switches adult cortical networks into a state of elevated plasticity within minutes by decreasing the intrinsic excitability of PV interneurons, recapitulating the effects of fluoxetine. TrkB activation shifted cortical networks towards a low PV configuration, promoting oscillatory synchrony, increased excitatory-inhibitory balance, and ocular dominance plasticity. OptoTrkB activation promotes the phosphorylation of Kv3.1 channels and reduces the expression of Kv3.2 mRNA providing a mechanism for the lower excitability. In addition, decreased expression and puncta of Synaptotagmin2 (Syt2), a presynaptic marker of PV interneurons involved in Ca2+-dependent neurotransmitter release, suggests lower inputs onto pyramidal neurons suppressing feed-forward inhibition. Together, the results provide mechanistic insights into how TrkB activation in PV interneurons orchestrates the activity of cortical networks and mediating antidepressant responses in the adult brain.
Highlights
Brain plasticity is a key process allowing learning throughout life and adjustment of maladapted networks underlying neuropsychiatric diseases
Recently it became apparent that the adult brain can still operate in different states of plasticity induced by interventions, such as antidepressant treatment and environmental enrichment [1,2,3]
Chronic treatment with the antidepressant fluoxetine, for example, induces juvenile-like plasticity in the adult brain, resulting in a shift of ocular dominance (OD) after monocular deprivation [1] and fear erasure when combined with extinction training [2]
Summary
Brain plasticity is a key process allowing learning throughout life and adjustment of maladapted networks underlying neuropsychiatric diseases. Chronic treatment with the antidepressant fluoxetine, for example, induces juvenile-like plasticity (iPlasticity) in the adult brain, resulting in a shift of ocular dominance (OD) after monocular deprivation [1] and fear erasure when combined with extinction training [2]. Brain-derived neurotrophic factor (BDNF) and its receptor Neurotrophic receptor tyrosine kinase 2 (Ntrk, TrkB) are critical regulators of neuronal plasticity [12]. 1234567890();,: Here, we use heterozygous conditional TrkB knockout mice and OptoTrkB infected mice that had their transparent skull painted black all targeted TrkB activation to show that activation of TrkB in cortical PV interneurons is critical for the regulation of cortical plasticity and antidepressant responses. Dynamically regulates the intrinsic properties of PV interneurons by decreasing their intrinsic excitability and switching the PV network into a plastic configuration, which orchestrates adult cortical plasticity states and mediates the effects of antidepressants on neuronal plasticity. Neuronal oscillations between 4 and 112 Hz were extracted by Morlet-wavelet filtering after normalization and current source density
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