Neuroglialpharmacology: myelination as a shared mechanism of action of psychotropic treatments

Abstract

Current psychiatric diagnostic schema segregate symptom clusters into discrete entities, however, large proportions of patients suffer from comorbid conditions that fit neither diagnostic nor therapeutic schema. Similarly, psychotropic treatments ranging from lithium and antipsychotics to serotonin reuptake inhibitors (SSRIs) and acetylcholinesterase inhibitors have been shown to be efficacious in a wide spectrum of psychiatric disorders ranging from autism, schizophrenia (SZ), depression, and bipolar disorder (BD) to Alzheimer's disease (AD). This apparent lack of specificity suggests that psychiatric symptoms as well as treatments may share aspects of pathophysiology and mechanisms of action that defy current symptom-based diagnostic and neuron-based therapeutic schema. A myelin-centered model of human brain function can help integrate these incongruities and provide novel insights into disease etiologies and treatment mechanisms. Available data are integrated herein to suggest that widely used psychotropic treatments ranging from antipsychotics and antidepressants to lithium and electroconvulsive therapy share complex signaling pathways such as Akt and glycogen synthase kinase-3 (GSK3) that affect myelination, its plasticity, and repair. These signaling pathways respond to neurotransmitters, neurotrophins, hormones, and nutrition, underlie intricate neuroglial communications, and may substantially contribute to the mechanisms of action and wide spectra of efficacy of current therapeutics by promoting myelination. Imaging and genetic technologies make it possible to safely and non-invasively test these hypotheses directly in humans and can help guide clinical trial efforts designed to correct myelination abnormalities. Such efforts may provide insights into novel avenues for treatment and prevention of some of the most prevalent and devastating human diseases.

Figure 1. Quadratic (inverted “U”) Myelination Trajectories of Human Brain Over the Lifespan

Human brain myelination (Y axis) across the age span (X axis). Frontal and temporal lobes (depicted on left and right figures respectively). Top figures are in vivo MRI data (from Bartzokis et al., 2001) showing significant quadratic relationships (p<.001) of myelinated white matter volumes (a measure that includes highly myelinated lower cortical layers). Intracortical myelin stain data are depicted in the lower figures (from Kaes, 1907) (adapted and reproduced in Kemper, 1994). Used with permission. The in vivo (top panels) and post-mortem (lower panels) samples of normal individuals show remarkably similar myelination trajectories demonstrating a dynamic myelin “plasticity” that does not peak until middle age. Note: even though the regions are similar, as is the case with these two late-myelinating association regions, myelination trajectories differ and peak at significantly different ages (p<.01) (Bartzokis et al., 2001).

Figure 2. The Human Brain “Internet” Establishes Synchronous Activity in Childhood Through Subcortical Myelination and Perfects it in Adulthood Through Intracortical Myelin (ICM)

Red arrows stand in for myelinated axons with fast transmission (more than 100 fold faster than unmyelinated axons). Insert depicts cortex of child (on left, unmyelinated) and adult (on right, myelinated). Subcortical myelination (accomplished in childhood) makes action potential transmission in circuits of markedly different lengths such as thalamo-frontal (long horizontal red arrow) and thalamoinsular (short down-pointing red arrow) very fast. Once the fast subcortical portion of a circuit is myelinated, the intracortical transmission of the action potential through unmyelinated axons (insert: blue arrow on left panel) takes much longer (10 fold longer than subcortical transmission). Thus, once subcortical myelination is established in childhood, the constant intracortical distance to layer III establishes a roughly synchronous arrival of action potentials to all layer III pyramidal neurons. Later in development and throughout adulthood, appropriate and region-specific myelination of the cortical portion of the axons (insert: red arrow on right panel) continually optimizes the synchrony of action potential arrival and thus optimizes cognitive and behavioral functions (see text for further details).

Figure 3. Neuroglialpharmacology of Psychiatric Treatments, Hormones, and Neurotrophins

Major classes of currently available psychotropic medications, other pharmacologic agents, and ECT (underlined) seem to share direct or indirect inhibition of GSK3 as a common mechanism of action. Many but not all GSK3 effects are shared by its α and β isoforms, however in many instances, specific isoform effects remain to be clarified. Indirect (through Akt activation) and direct GSK3β inhibition promotes myelination by releasing the negative control GSK3β has on myelination. Some neurotrophins (NRG & BDNF), hormones (IGF1, T3, TRH), and cytokines (leptin) also seem to inhibit GSK3. Conversely, some drugs of abuse with known cognitive and behavioral toxicities (cocaine, methamphetamine, PCP) seem to have the opposite (GSK3 activation) effect and would be expected to share inhibition of myelination as a potential detrimental effect on brain function. Some GSK3-dependent myelin interactions of the dopaminergic, serotinergic, glutaminergic, and cholinergic system are depicted in this figure, however the GABAergic ones are not (see text for details). An asterisk denotes genes known to be associated with increased risk for schizophrenia (SZ) and/or bipolar disorder (BD). Note: as a schematic focused on the key role of GSK3 on myelination, this figure does not depict many additional relationships such as the ones between GSK3 and other kinases (mTOR, MAPK, Cdk), genes, nutrition, metabolism, environment, and epigenetic changes and the interdependence of all CNS cell types and their specialized structures such as synapses. For further details on these topics please refer to the text and reference list.