Hippocampal Hyperactivity as a Druggable Circuit-Level Origin of Aberrant Salience in Schizophrenia

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.

Keywords: CA3; aberrant salience; attention; glutamate hypothesis; hippocampus; mesolimbic; schizophrenia; subiculum.

Figure 1

A circuit-neuroscience approach to drug discovery. Combining the optogenetic or chemogenetic modulation (Tye and Deisseroth, 2012; Deisseroth, 2014; Sternson and Roth, 2014) and imaging (Grewe et al., 2017; Ghosh et al., 2011) of genetically specified cell-types with behavioral testing in rodents, the brain areas, cell-types, specific projections, and potentially even signaling cascades that underlie certain cognitive functions can be identified (Kätzel and Kullmann, 2015). As a next step, genes selectively expressed in the identified cell-types can be revealed (Saunders et al., 2018; Tasic et al., 2018), which modulate neuronal activity. The proteins encoded by such genes can be ablated in these genetically specified cell-types using e.g. CRISPR/Cas9 (Swiech et al., 2015), or modulated systemically by pharmacology to validate their suitability as molecular treatment targets.

Figure 2

Ventral hippocampal projections that regulate dopamine neuron activity and release. Different, but interacting circuits have been found to regulate dopaminergic signaling by the ventral tegmental area (VTA) (see main text and Tables 1-3 for description and references): projections from the ventral subiculum (vSub, the output region of the vHC) target the VTA through the bed nucleus of the stria terminalis (BNST), the amygdala or through the ventral basal ganglia comprising the nucleus accumbens (NAc) and the ventral pallidum (VP) thereby determining the number of active dopamine neurons. Additional input from the pedunculo-pontine tegmental nucleus (PPTN) and the latero-dorsal tegmental nucleus (LDTN) determine if these active neurons enter into burst-firing mode with ensuing phasic dopamine release in the NAc. The PPTN is modulated indirectly by the vSub→NAc pathway via neurons in the subpallidal region (SP), comprising part of the VP, the lateral hypothalamus, and the substantia innominata. Medial septal (MS, blue) and prefrontal influences (green) from the infralimbic (IL) and anterior cingulate (ACC) cortex onto dopaminergic neurons act centrally through the vSub as well, but also through the NAc, BNST, and amygdala; the ACC also innervates the dorsomedial (associative) striatum (dmS) which has gained increasing attention as a key target of dopaminergic midbrain projections aside from the ventral striatum (NAc).

Figure 3

Dorsal hippocampal and septal projections that regulate dopamine neuron activity. Extension of Figure 2, additionally showing prominent connections from the dorsal CA3-subfield (dCA3), encoding contextual information from the neocortex (NC) transmitted through the entorhinal cortex (EC) and dentate gyrus (DG), to the lateral septum (LS). A further link between the dCA3 and the vSub circuit is mediated via dorsal CA1 (dCA1) and the nucleus reuniens (NRe).