Potential synergistic action of 19 schizophrenia risk genes in the thalamus

Abstract

A goal of current schizophrenia (SZ) research is to understand how multiple risk genes work together with environmental factors to produce the disease. In schizophrenia, there is elevated delta frequency EEG power in the awake state, an elevation that can be mimicked in rodents by N-methyl-d-aspartate receptor (NMDAR) antagonist action in the thalamus. This thalamic delta can be blocked by dopamine D2 receptor antagonists, agents known to be therapeutic in SZ. Experiments suggest that these oscillations can interfere with brain function and may thus be causal in producing psychosis. Here we evaluate the question of whether well-established schizophrenia risk genes may interact to affect the delta generation process. We identify 19 risk genes that can plausibly work in a synergistic fashion to generate delta oscillations.

Keywords: Delta oscillations; Dopamine receptor hyperfunction; NMDAR hypofunction; Nucleus reticularis; Relay cells; Schizophrenia.

Fig. 1. Nineteen risk genes for schizophrenia may affect delta generation in the thalamus

In the thalamus, inhibitory cells of the nRT interact with excitatory relay cells of thalamic nuclei. For ease of visualization, risk genes that affect glutamatergic function (NMDA hypofunction), dopamine hyperfunction, and delta generation are placed against different background colors. The lower-left inset shows the layout of the nRT. Genes are 1) T T-type calcium channel (CaV3.3); 2,3) L L-type calcium channel (CaV1.2 alpha subunit or CaVB2 beta subunit); 4) SERCA sarcoplasmic/endoplasmic reticulum Ca transporting ATPase (ATP2A2); 5) HCN1 hyperpolarization-activated, cyclic-nucleotide gate K channel 1 (HCN1); 6) GRM3 glutamate receptor metabotropic 3; 7) D2 dopamine receptor D2 (DRD2); 8) DGCR8 DiGeorge critical region 8; 9) COMT catechol-O-methyl transferase; 10) Serine racemase (SRR); 11) GSTT2 glutathione-S-transferase theta 2; 12) MSRA methionine sulfoxide reductase A; 13) DISC1 disrupted in schizophrenia 1; 14) ARC activity-regulated cytoskeleton-associated protein; 15) GluA1 glutamate ionotropic AMPA receptor 1 (GRIA1); 16) Erbb4 erb-b2 receptor tyrosine kinase 4; 17) SAP-97 synapse-associated protein 97 (DLG1); 18) PSD-93 postsynaptic density protein 93 (DLG2); 19) CHRNA3 Cholinergic receptor nicotinic alpha 3 subunit. Also shown are GluA4, DAO, NR2C and NR2A, which are relevant to thalamic function, but have not been strongly implicated in the disease by genetic studies. DAO D-amino acid oxidase; GluA4 glutamate ionotropic AMPAR subunits; NR2A or NR2C glutamate ionotropic NMDA receptor subunits; neuregulin is shown in this figure because of its role in the control of thalamic function (Ahrens et al., 2015). SOM somatostatin interneuron. The list at bottom right gives the symptoms of SZ that may be linked to thalamic dysfunction in SZ: attentional gating (Behrendt, 2003), hyperactivation of CA1 (Schobel et al., 2009; Zhang et al., 2012b), elevated delta power (Clementz et al., 1994), delta jamming (Duan et al., 2015), and lowered auditory input (Chun et al., 2014). Note that the proportions in this figure do not reflect the actual sizes of the nRT and thalamic relay nuclei. Also note that, while some of these genes displayed in the nRT are also present in relay nuclei, and vice versa, we only show where the genes are preferentially expressed.