The role of neurotrophic factors in novel, rapid psychiatric treatments

Abstract

Neurotrophic factors are a family of growth factors that modulate cellular growth, survival, and differentiation. For many decades, it has been generally believed that a lack of neurotrophic support led to the decreased neuronal synaptic plasticity, death, and loss of non-neuronal supportive cells seen in neuropsychiatric disorders. Traditional psychiatric medications that lead to immediate increases in neurotransmitter levels at the synapse have been shown also to elevate synaptic neurotrophic levels over weeks, correlating with the time course of the therapeutic effects of these drugs. Recent advances in psychiatric treatments, such as ketamine and psychedelics, have shown a much faster onset of therapeutic effects (within minutes to hours). They have also been shown to lead to a rapid release of neurotrophins into the synapse. This has spurred a significant shift in understanding the role of neurotrophins and how the receptor tyrosine kinases that bind neurotrophins may work in concert with other signaling systems. In this review, this renewed understanding of synaptic receptor signaling interactions and the clinical implications of this mechanistic insight will be discussed within the larger context of the well-established roles of neurotrophic factors in psychiatric disorders and treatments.

Fig. 1. Schematic of the excitatory glutamatergic neuronal synapse highlighting the effects of various psychiatric treatments on BDNF transport, release, and synthesis.

With the inhibition of NMDARs by ketamine, the phosphorylation of eukaryotic elongation factor 2 (eEF2) is blocked. This alleviates the inhibition on BDNF translation, resulting in rapid BDNF protein synthesis and subsequent AMPAR-mediated increases in BDNF levels. Psychedelics, more specifically psilocybin/psilocin and LSD, lead to increases in extracellular glutamate, sustained AMPAR activation, and rapid BDNF production. There is also emerging evidence that both ketamine and psychedelics may directly bind to the TrkB transmembrane domain to potentiate BDNF-mediated signaling. N₂O, another NMDAR antagonist, has been shown to increase BDNF levels; however, there is insufficient evidence to conclude that the molecular mechanism is like ketamine’s mechanism. ECT has more broad effects, but it has been specifically shown to increase BDNF mRNA, including proBDNF and mature BDNF levels, in rodent models. Ibogaine has a diverse profile of receptor agonism and antagonism, and its mechanism of action as it relates to the neurotrophic systems is actively under investigation. Currently, it is known that ibogaine leads to increases in both BDNF and GDNF levels in preclinical models. In terms of new mechanistic insight into the role of neurotrophic systems in rapid-acting psychiatric treatments, there is emerging evidence that post-synaptic crosstalk between TrkB and metabotropic glutamate receptor 5 (mGluR5) can affect intracellular calcium signaling to modulate BDNF-induced synaptic potentiation and synaptogenesis.