Abstract
The development of current neuroleptics was largely aiming to decrease excessive dopaminergic signaling in the striatum. However, the notion that abnormal dopamine creates psychotic symptoms by causing an aberrant assignment of salience that drives maladaptive learning chronically during disease development suggests a therapeutic value of early interventions that correct salience-related neural processing. The mesolimbic dopaminergic output is modulated by several interconnected brain-wide circuits centrally involving the hippocampus and key relays like the ventral and associative striatum, ventral pallidum, amygdala, bed nucleus of the stria terminalis, nucleus reuniens, lateral and medial septum, prefrontal and cingulate cortex, among others. Unraveling the causal relationships between these circuits using modern neuroscience techniques holds promise for identifying novel cellular—and ultimately molecular—treatment targets for reducing transition to psychosis and symptoms of schizophrenia. Imaging studies in humans have implicated a hyperactivity of the hippocampus as a robust and early endophenotype in schizophrenia. Experiments in rodents, in turn, suggested that the activity of its output region—the ventral subiculum—may modulate dopamine release from ventral tegmental area (VTA) neurons in the ventral striatum. Even though these observations suggested a novel circuit-level target for anti-psychotic action, no therapy has yet been developed along this rationale. Recently evaluated treatment strategies—at least in part—target excess glutamatergic activity, e.g. N-acetyl-cysteine (NAC), levetiracetam, and mGluR2/3 modulators. We here review the evidence for the central implication of the hippocampus-VTA axis in schizophrenia-related pathology, discuss its symptom-related implications with a particular focus on aberrant assignment of salience, and evaluate some of its short-comings and prospects for drug discovery.
Highlights
Specialty section: This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology
While numerous major brain regions have been implicated in schizophrenia—including the neocortex, thalamus, and cerebellum which were not highlighted here— singling out the hippocampus as a potential therapeutic target seems justified by the robustness of its aberrations in schizophrenia and its validated role in controlling dopaminergic signaling
The vast complexity of the brain-wide circuit controlling dopamine (Figure 3) may entail the risk that interventions targeted at one region are outweighed by pathologies in another one, and even that among schizophrenia patients there is enormous heterogeneity, with subpopulations in whom aberrant salience may be unrelated to the hippocampus and which would remain unresponsive to such a therapy
Summary
A key question concerns what specific role the hippocampus has in determining the dopaminergic salience signal. Two key empirical results supported her model: firstly, individual neurons in CA1 habituate their sensory-evoked responses with repeated presentation of the same stimulus [akin to the short-term habituation of CA1BOLD in humans discussed above, (Holt et al, 2005)]; and secondly, this habituation was abolished and the response to familiar stimuli increased—(i.e. sensitized)—if CA1 was disconnected from CA3 (i.e. Schaffer collaterals were severed in vivo) (Vinogradova, 2001) In this view, the hippocampus detects matches or mismatches between expectations based on previous sensory experience (memories) and current sensory input, thereby computing a saliency or prediction error signal which would be relayed to the VTA (Vinogradova, 2001). Such cellular targets can be translated into molecular targets by cell-type specific gene expression analysis to identify selectively expressed genes that modulate their neural activity
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