Cholinergic Circuits and Signaling in the Pathophysiology of Schizophrenia

Abstract

Central cholinergic signaling has long been associated with aspects of memory, motivation, and mood, each affected functions in neuropsychiatric disorders such as schizophrenia. In this chapter, we review evidence related to the core hypothesis that dysregulation of central cholinergic signaling contributes to the pathophysiology of schizophrenia. Although central cholinergic circuits are resistant to simplification-particularly when one tries to parse the contributions of various classes of cholinergic receptors to disease related phenomena-the potential role of ACh signaling in Schizophrenia pathophysiology deserves careful consideration for prospective therapeutics. The established role of cholinergic circuits in attentional tuning is considered along with recent work on how the patterning of cholinergic activity may modulate corticostriatal circuits affected in schizophrenia.

Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model

“…Taken together with previous clinical studies in schizophrenia patients and preclinical studies in rodent models, these data form a strong argument for the functional relevance of muscarinic plasticity in schizophreniarelated behavioral deficits and support the hypothesis that highly selective M 1 PAMs may provide therapeutic efficacy in treatment of some aspects of the negative and cognitive symptoms in schizophrenia patients. The present findings are especially interesting in light of multiple previous studies that cholinergic signaling Role of M 1 PAM in PCP-treated mice A Ghoshal et al is disrupted in the PFC and other cortical and limbic forebrain regions of schizophrenia patients (Berman et al, 2007;Dean et al, 2002;Raedler et al, 2007;Scarr et al, 2009a;Zavitsanou et al, 2004). Of particular interest is the recent finding that a defined subset of schizophrenia patients display decreases in M 1 levels in PFC and other cortical and forebrain regions (Dean et al, 2002;Gibbons et al, 2013).…”

“…Interestingly, multiple studies suggest that cholinergic signaling is disrupted in schizophrenia patients and in animal models of schizophrenia (Berman et al, 2007;Dean et al, 2002;Scarr and Dean, 2009b;Zavitsanou et al, 2004). If these changes in cholinergic signaling lead to impairments in muscarinic LTD (mLTD), this could contribute to the underlying pathophysiology in PFC function.…”

Cognitive Deficits in Schizophrenia: Focus on Neuronal Nicotinic Acetylcholine Receptors and Smoking

“…Cholinergic pathways have been implied as participating in the physiopathology of schizophrenia (for a recent review see Berman et al 2007). Furthermore, neuronal nAChRs have been implicated in the pathogenesis of some deficits seen in schizophrenic patients (Freedman et al 1994).…”

Pharmacological Strategies for Enhancing Cognition in Schizophrenia

“…Nonetheless, there are studies suggesting a range of impairments in the cholinergic system in schizophrenia, including alterations in choline acetyltransferase (Powchik et al 1998), and both nicotinic and muscarinic receptors (Breese et al 2000;Crook et al 1999Crook et al , 2000Crook et al , 2001Deng and Huang 2005;Griffith et al 1998;Scarr et al 2009) in the brains of individuals with schizophrenia (for reviews, see Adams and Stevens 2007;Berman et al 2007;Martin and Freedman 2007;Terry 2008).…”