Signaling pathways in schizophrenia: emerging targets and therapeutic strategies

Abstract

Dopamine D2 receptor antagonism is a unifying property of all antipsychotic drugs in clinical 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 a number 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/ERB4, and components of the Akt/GSK-3 pathway.

A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health

“…[108][109][110] This is particularly intriguing since altered glutamate receptor functions have long been suspected to play a role in mental disorder pathology, mostly in schizophrenia. 73,111 However, it would be premature to conclude that the role of Akt-GSK3 signalling is restricted to the regulation of glutamate receptor functions.…”

Heteromeric Dopamine Receptor Signaling Complexes: Emerging Neurobiology and Disease Relevance

“…Further support for a potential role for the D1-D2 heteromer in schizophrenia comes from a recent finding demonstrating that activation of the D1-D2 receptor heteromer could inactivate glycogen synthase kinase-3b (GSK-3b) in rodent prefrontal cortex (PFC) (Perreault et al, 2013) (Figure 1). In schizophrenia, cortical GSK-3b activation is upregulated (Emamian et al, 2004) and has been implicated as contributing to cognitive dysfunction in the disorder Karam et al, 2010). This suggests potential for D1-D2 heteromer activation as a therapeutic intervention to normalize cortical GSK-3b levels in schizophrenia patients, with potential consequential improvements in cognitive performance.…”

The Presynaptic Component of the Serotonergic System is Required for Clozapine's Efficacy

“…These include targeting various components of the glutamate synapse (eg, mGluR2/3 allosteric potentiators, mGluR5 potentiators, GlyT1 glycine transporter inhibitors, and AMPA receptor potentiators), nicotinic acetylcholine subtype-selective agents, phosphodiesterase 10A inhibitors, NK3-neurokinin receptor antagonists, and others (Conn and Roth, 2008;Gray and Roth, 2007;Karam et al, 2010). At present, it is unknown which, if any, of the above mechanistically designed (or single-target-based) approaches to treat schizophrenia require an intact presynaptic serotonergic neuronal system, although we are actively engaged in evaluating many of these drugs in pet1 À/À mice (PN Yadav et al, unpublished).…”