Signaling pathways in schizophrenia: emerging targets and therapeutic strategies

Abstract

Dopamine D(2) receptor antagonism is a unifying property of all antipsychotic drugs in use for schizophrenia. While often effective at ameliorating psychosis, these drugs are largely ineffective at treating negative and cognitive symptoms. Increasing attention is being focused on the complex genetics of the illness and the signaling pathways implicated in its pathophysiology. We review targeted approaches for pharmacotherapy involving the glutamatergic, GABAergic and cholinergic pathways. We also describe several of the major genetic findings that identify signaling pathways representing potential targets for novel pharmacological intervention. These include genes in the 22q11 locus, DISC1, Neuregulin 1/ErbB4, and components of the Akt/GSK-3 pathway.

Figure 1. Dopamine D₂receptor antagonism as a unifying property of all antipsychotic drugs in clinical use

Current antipsychotic medications are thought to alleviate symptoms by blocking dopamine (DA) D₂ receptor (D₂R) activation and blunting dopaminergic signaling. Binding of DA to D₂R results in G-protein dependent and G-protein-independent signaling. The DA D₂R couples to G_i/o G-proteins to inhibit adenylate cyclase and also to modulate voltage-gated K⁺ and Ca²⁺ channels. DA binding also inhibits Akt activity in a G-protein-independent manner by recruitment of the scaffolding protein β-arrestin-2, which in turn recruits Akt and the phosphatase, PP2A. PP2A dephosphorylates Akt, leading to its inactivation and enhanced activity of the downstream kinase GSK-3.

Figure 2. Glutamaergic and GABAergic Signaling

GABA receptors mediate activity in the dorsolateral prefrontal cortex (DLPFC), which plays an important role in working memory. GABA production is controlled by glutamate decarboxylase GAD67, the expression of which is decreased in patients with schizophrenia. Altered expression patterns of GABA transporter (GAT1) and the GABA_A receptor alpha 2 subunit (GABA_Aα2) have also been observed, and α2-positive allosteric modulators are being explored for therapeutic benefits. Decreased GABA contributes to worsening of the synchronization of pyramidal cells, which is thought to contribute to deficits in working memory. Deficits in glutamatergic signaling have also been implicated in schizophrenia. Blocking the glycine transporter (GlyT) can increase the amount of the allosteric potentiator glycine that is available to the NMDA receptor (NR1/2) and enhance NMDA neurotransmission, as can D-serine, and D-cycloserine. A type II (2/3) mGluR agonist has shown initial promise in decreasing both positive and negative symptoms, although this has not been replicated. Positive allosteric modulators of mGluR5 have shown promise in animal models. Adapted with permission from Lewis and Moghaddam, Archives of Neurology 63, 1372–1376, copyright © 2006 American Medical Association. All rights reserved.

Figure 3. Cholinergic Signaling

(A) Expression profile of nicotinic and muscarinic receptors within structures associated with schizophrenia (squares) and areas projecting to these structures. Green: excitatory receptors; Red: inhibitory receptor; MS: medial septum; NBM: nucleus basalis of meynert; MT: mesopontine tegmentum; SN substantia nigra pars compacta; VTA: ventral tegmental area. Although it has been very difficult to target specific muscarinic receptors with drugs, the recent identification of highly specific allosteric modulators of multiple receptor subtypes will make it possible to explore targeted pharmacotherapies. (B) Intracellular signaling associated with nicotinic receptor alpha 7 (nAChR α7) and the G-protein-coupled muscarinic receptor M1. nAChR α7 has high permeability for Ca²⁺ ions and channel opening promotes Ca²⁺ influx from the extracellular milieu and subsequent activation of Ca²⁺-associated signals. M1 signal is mediated by the Gq/11-PLC pathway, which includes activation of PKC and Ca²⁺-associated signaling. α7 agonists have shown potential promise in treating negative and cognitive symptoms, but rapid receptor desensitization makes this a difficult target.

Figure 4. The 22q11 locus

This 1.5 megabase region is flanked by low-copy repeat sequences (light blue boxes) making it prone to nonhomologous recombination. Approximately 30% of all individuals with 22q11.3 microdeletions develop symptoms of schizophrenia. Three schizophrenia candidate genes in this region are highlighted in bold font: proline dehydrogenase, PRODH, catechol-O-methyltransferase, COMT, and a palmitoyl-transferase, ZDHHC8. PRODH-P and DGRC6-like are pseudogenes. Adapted with permission from Dr. Alexander Arguello and Dr. Joseph Gogos, Department of Physiology and Cellular Biophysics, Columbia University, New York, NY.

Figure 5. Neuregulin (NRG1) Isoforms and ErbB (EGF receptor tyrosine kinase) signaling pathways

More than 80 SNPs within the Erb4/NRG1 receptor/ligand pair have been associated with schizophrenia. All NRG1 isoforms signal through an EGF domain, either through paracrine, juxtacrine, or autocrine mechanisms. ErbB2, ErbB3, and ErbB4 form dimers and heterodimers, which signal through multiple pathways. Classical signals are transduced through the Grb2 and Shc adaptor molecules and the Raf–MEK–ERK, or JUN kinase cascade to activate transcription factors such as GABP, SRF, and c-jun. Also activated are the PI3K, AKT, mTOR pathway. Brain-specific receptor-type proteintyrosine phosphatase, RPTP-beta, modulates ErbB4 signals through an interaction with MAGI proteins. Additionally, ErbB4 colocalizes with PSD95 and may modulate NMDA, AMPA, and metabotropic glutamate receptor function. The non-cannonical ErbB signals are transmitted by a cleaved ErbB intracellular domain (EICD), which translocates to the nucleus and interacts with nuclear transcription factors. Three ErbB signaling pathways overlap with the disrupted in Schizophrenia 1, DISC1, interactome, namely, AKT-mTOR, EICD, and PSD95 mediated signals.

Figure 6. Disrupted in Schizophrenia1 (DISC1)

Disrupted in schizophrenia (DISC1) is a gene locus originally identified in a Scottish family, many of whom carried a balanced translocation between chromosomes 1 and 11 and who had a high frequency of psychiatric disorders, including schizophrenia, bipolar disorder, and recurrent major depression. Linkage and association studies have also supported a role for the DISC1 locus in schizophrenia. DISC1 associates with important cellular components, including the centrosome, microtubules, terminals and neurite growth cones, enabling it to play a role in various cellular functions, such as neuronal migration and axonal elongation, as well as microtubule transport and organization. Note that DISC1 can also inhibit GSK-3 activity, and thus potentially overlaps with dopaminergic signaling and NRG1/ERB4 signaling. Adapted with permission from Macmillan Publishers Ltd: Molecular Psychiatry (Chubb et al. [2008] Mol. Psych. 13, 36–64), copyright 2008.