Abstract
Cognitive deficits in individuals with schizophrenia (SCZ) are considered core symptoms of this disorder, and can manifest at the prodromal stage. Antipsychotics ameliorate positive symptoms but only modestly improve cognitive symptoms. The lack of treatments that improve cognitive abilities currently represents a major obstacle in developing more effective therapeutic strategies for this debilitating disorder. While D4 receptor (D4R)-specific antagonists are ineffective in the treatment of positive symptoms, animal studies suggest that D4R drugs can improve cognitive deficits. Moreover, recent work from our group suggests that D4Rs synergize with the neuregulin/ErbB4 signaling pathway, genetically identified as risk factors for SCZ, in parvalbumin (PV)-expressing interneurons to modulate gamma oscillations. These high-frequency network oscillations correlate with attention and increase during cognitive tasks in healthy subjects, and this correlation is attenuated in affected individuals. This finding, along with other observations indicating impaired GABAergic function, has led to the idea that abnormal neural activity in the prefrontal cortex (PFC) in individuals with SCZ reflects a perturbation in the balance of excitation and inhibition. Here we review the current state of knowledge of D4R functions in the PFC and hippocampus, two major brain areas implicated in SCZ. Special emphasis is given to studies focusing on the potential role of D4Rs in modulating GABAergic transmission and to an emerging concept of a close synergistic relationship between dopamine/D4R and neuregulin/ErbB4 signaling pathways that tunes the activity of PV interneurons to regulate gamma frequency network oscillations and potentially cognitive processes.
Highlights
Schizophrenia (SCZ) is characterized by three distinct symptom clusters – positive, negative, and cognitive
6-hydroxydopamine-mediated hyperactivity is absent in Drd4−/− mice (Avale et al, 2004). These findings strongly suggest a role for the D4 receptor (D4R) in mediating behavioral responses to perturbed DA function in the striatum, it remains unclear if these effects originate, as suggested, in a hyperexcitable prefrontal cortex (PFC) or elsewhere, and what molecular and cellular D4R-dependent processes underlie them
Acute pharmacological inhibition of D4R in the rat medial PFC (mPFC) by L-745,870 injection was shown to be anxiolytic in the elevated plus maze and shock-probe burial test (Shah et al, 2004). These findings suggest that the D4R is involved in emotional learning, but that the effects of receptor interference depend on the experimental approach utilized
Summary
Schizophrenia (SCZ) is characterized by three distinct symptom clusters – positive, negative, and cognitive. The D4R agonists A-412997 and PD168077 enhance memory for aversive stimuli according to an inverted U-shaped curve (Browman et al, 2005), but have shown linear increases in working memory performance in a similar procedure and a novel object recognition paradigm (Bernaerts and Tirelli, 2003; Woolley et al, 2008) Taken together, these results suggest that the D4R mediates memory consolidation of both normal and emotionally salient experiences, and that the intensity of the stimulus interacts with DA signaling through D4Rs. EXPRESSION IN FS PARVALBUMIN INTERNEURONS A number of studies have found D4R mRNA and protein in PV interneurons of both the PFC and the hippocampus.
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