|The Role of Ankyrin-G in Mental Disorders||MT|
In a brain, two distant regions are said to be "functionally connected" if stimulation of one region can induce neural activity in another region via long range synchronization. Mental disorders arise from impairment in functional connectivity (Fornito and Harrison, 2012). According to the Wireless Model (Chapter 6), long range synchronization could be mediated by electromagnetic coupling which can be achieved by anchoring microtubules to the membrane through Ankyrin-G (Chapter 7). Interestingly, Ankyrin-G (encoded by the ANK3 gene) is associated with most mental disorders: Alzheimer's disease (Morgan et al., 2008), attention deficit hyperactivity disorder (ADHD) (Iqbal et al., 2013), autism (Bi et al., 2012), bipolar disorder (Schulze et al., 2009), posttraumatic stress (Logue et al., 2013) and schizophrenia (Athanasiu et al., 2010).
Functional Connectivity in Mental Disorders
In experiments, functional connectivity can be revealed by functional magnetic resonance imaging (fMRI) or magnetoencephalographic (MEG) connectivity dynamics. Figure 1 shows the results of MEG studies on brain activities during number estimation tasks for both healthy and autistic participants. Long range synchronization at the beta band is significantly reduced in participants with autism.
Brain waves are divided into several frequency bands. The beta band (16 - 40 Hz) synchrony enhances task-relevant neural activities while the alpha band (8 - 15 Hz) synchrony suppresses task-irrelevant activities (Buschman et al., 2012). Reduction of the alpha power is a defining feature of ADHD (Woltering et al., 2012). Schizophrenia arises from abnormal synchronization at beta and gamma (> 40 Hz) bands (Uhlhaas and Singer, 2010).
Hyperexcitability by ANK3 Mutation
The ANK3 gene, which encodes Ankyrin-G, is implicated in most mental disorders. Its mutation may produce two different types of abnormalities. (1) Modification of protein structure that disrupts its association with the membrane or microtubule. (2) Alteration of gene expression that reduces the protein level (Roussos et al., 2012). Either abnormality may cause the microtubule to bend away from the membrane, thereby increasing neuronal excitability (see Chapter 7). Hence, ANK3 mutation may increase local neural activity, but the long range synchronization is impaired. This explains why a number of mental disorders exhibit "long-range under-connectivity and short-range over-connectivity" (Kern et al., 2015).
Elevation of excitation has been proposed as the major cause of autism (Rubenstein and Merzenich, 2003). This hypothesis is supported by experiments on mouse, demonstrating that social dysfunction can be induced simply by elevating excitation (Yizhar et al., 2011). Hyperexcitability has also been observed in Alzheimer's disease (Dickerson et al., 2005; Wesson et al., 2011), which is associated with decreased level of Ankyrin-G (Sun et al., 2014).
Author: Frank Lee