Neuroplasticity to autophagy cross-talk in a therapeutic effect of physical exercises and irisin in ADHD

Abstract

Adaptive neuroplasticity is a pivotal mechanism for healthy brain development and maintenance, as well as its restoration in disease- and age-associated decline. Management of mental disorders such as attention deficit hyperactivity disorder (ADHD) needs interventions stimulating adaptive neuroplasticity, beyond conventional psychopharmacological treatments. Physical exercises are proposed for the management of ADHD, and also depression and aging because of evoked brain neuroplasticity. Recent progress in understanding the mechanisms of muscle-brain cross-talk pinpoints the role of the myokine irisin in the mediation of pro-cognitive and antidepressant activity of physical exercises. In this review, we discuss how irisin, which is released in the periphery as well as derived from brain cells, may interact with the mechanisms of cellular autophagy to provide protein recycling and regulation of brain-derived neurotrophic factor (BDNF) signaling via glia-mediated control of BDNF maturation, and, therefore, support neuroplasticity. We propose that the neuroplasticity associated with physical exercises is mediated in part by irisin-triggered autophagy. Since the recent findings give objectives to consider autophagy-stimulating intervention as a prerequisite for successful therapy of psychiatric disorders, irisin appears as a prototypic molecule that can activate autophagy with therapeutic goals.

Keywords: ADHD; BDNF; autophagy; irisin; neuroplacticity; physical exercises.

Figure 1

Autophagy flux. Autophagy is a pivotal mechanism of cellular homeostasis. It is triggered by chemical stress and its flux is regulated by multiple cellular signaling pathways. Autophagy strongly depends on the activity of mTORC1. Unc-51 like autophagy activating kinase (ULK1) and Becline1 are essential initiators of autophagosome formation. Cargo specificity is conferred by autophagic receptors that recognize specific target (proteins and other macromolecules), linked to p62, for degradation and microtubule-associated protein 1A/1B-light chain 3 LC3. Autolysosomes are docked to cellular membranes with subsequent devastation and release of cargo.

Figure 2

The pathway of irisin synthesis and its main cellular targets. By muscle activation, the peroxisome proliferator-activated receptor gamma (PPAR-γ) activates the PPAR receptors by giving rise to peroxisome proliferator-activated receptor gamma coactivator 1-alpha—estrogen-related receptor alpha (PGC1-α/ERRα) transcription factors for fibronectin type III domain-containing protein 5 (FNDC5) transcription. FNDC5 appears as precursor of irisin. Released Irisin accesses different organs, including brain, where it acts as an indirect stimulator of neuroplasticity.

Figure 3

Molecular targets of irisin. There is a number of the intracellular cascades are shown to respond to irisin both in vitro and in vivo: However, the exact mechanism providing a coupling of free irisin and its intracellular targets is still unknown. AMPK, 5’ AMP-activated protein kinase; Frizzle/Wnt, key proteins of respective pathway; Insulin Rs, Trk insulin Receptors; mTORC1, mammalian target of rapamycin complex 1; PKB, protein kinase B (Akt); and UCP2, uncoupled protein 2.