Erbb4Deletion From Inhibitory Interneurons Causes Psychosis-Relevant Neuroimaging Phenotypes

Abstract

Background and Hypothesis Converging lines of evidence suggest that dysfunction of cortical GABAergic inhibitory interneurons is a core feature of psychosis. This dysfunction is thought to underlie neuroimaging abnormalities commonly found in patients with psychosis, particularly in the hippocampus. These include increases in resting cerebral blood flow (CBF) and glutamatergic metabolite levels, and decreases in ligand binding to GABAA α5 receptors and to the synaptic density marker synaptic vesicle glycoprotein 2A (SV2A). However, direct links between inhibitory interneuron dysfunction and these neuroimaging readouts are yet to be established. Conditional deletion of a schizophrenia susceptibility gene, the tyrosine kinase receptor Erbb4, from cortical and hippocampal inhibitory interneurons leads to synaptic defects, and behavioral and cognitive phenotypes relevant to psychosis in mice. Study Design Here, we investigated how this inhibitory interneuron disruption affects hippocampal in vivo neuroimaging readouts. Adult Erbb4 conditional mutant mice (Lhx6-Cre;Erbb4F/F, n = 12) and their wild-type littermates (Erbb4F/F, n = 12) were scanned in a 9.4T magnetic resonance scanner to quantify CBF and glutamatergic metabolite levels (glutamine, glutamate, GABA). Subsequently, we assessed GABAA receptors and SV2A density using quantitative autoradiography. Results Erbb4 mutant mice showed significantly elevated ventral hippccampus CBF and glutamine levels, and decreased SV2A density across hippocampus sub-regions compared to wild-type littermates. No significant GABAA receptor density differences were identified. Conclusions These findings demonstrate that specific disruption of cortical inhibitory interneurons in mice recapitulate some of the key neuroimaging findings in patients with psychosis, and link inhibitory interneuron deficits to non-invasive measures of brain function and neurochemistry that can be used across species.

Transcriptional and neurochemical signatures of cerebral blood flow alterations in schizophrenia and the clinical high-risk state for psychosis

“…Our findings also highlight further relatively less-established molecular determinants in SSD, CHR-P and CHR-T individuals. These findings provide new evidence for established theories that the cellular and molecular basis of rCBF phenotypes in psychosis relate to GABAergic/glutamatergic alterations [38][39][40][41][42] , abnormalities in dopaminergic signalling 9 , and white matter integrity 43 . With ASL being a technique known to be sensitive to drug-induced changes to specific neurotransmitter systems 19,20 , this technique may be particularly well suited to highlight potential biological targets for intervention.…”

Modelling the overlap and divergence of autistic and schizotypal traits on hippocampal subfield volumes and regional cerebral blood flow

“…Also, glutamate levels in the hippocampus correlated inversely with hippocampal volumes in unmedicated first-episode psychosis [ 85 ]. Finally, a recent mouse model of ErbB4 mutants demonstrated that dysfunctional inhibitory interneurons may drive increased CBF and glutamine levels in the ventral hippocampus, while glutamate and GABA levels remained unchanged [ 43 ]. While timing and extent of structural and perfusion changes in the hippocampus may differ between subjects with psychosis and individuals with schizotypal traits, our study suggests that this link is also relevant in autism albeit with a different pattern.…”

“…Increased cerebral blood flow/volume are also found in subjects with early psychosis [ 41 , 42 ], thus rendering increased cerebral blood flow/volume an interesting marker of emerging and early psychosis. Most recently, a mouse model of ErbB4 mutants—a schizophrenia susceptibility gene—suggests that dysfunctional inhibitory interneurons drive increased cerebral blood flow and glutamine levels in the ventral hippocampus [ 43 ].…”

Effects of Diazepam on Hippocampal Blood Flow in People at Clinical High Risk for Psychosis

“…This would render the hippocampus dysrhythmic and hyperactive 14 , and excessive glutamatergic output 15–18 from the hippocampus to the striatum, amygdala, and prefrontal cortex may underlie the development of positive, negative, and cognitive symptoms, respectively 19 . Preclinical findings in the well-validated methylazoxymethanol acetate (MAM) rodent model of neurodevelopmental disruption 20–22 indicate that a loss of hippocampal parvalbumin-expressing (PV+) inhibitory interneurons 23 leads to hippocampal hyperactivity 24,25 , as measured with electrophysiology. Rodent models have also shown that selective reduction in PV mRNA expression 26 or knock-out of PV+ interneuron expression 24,25 are each sufficient to induce hippocampal hyperactivity.…”

“…Preclinical findings in the well-validated methylazoxymethanol acetate (MAM) rodent model of neurodevelopmental disruption 20–22 indicate that a loss of hippocampal parvalbumin-expressing (PV+) inhibitory interneurons 23 leads to hippocampal hyperactivity 24,25 , as measured with electrophysiology. Rodent models have also shown that selective reduction in PV mRNA expression 26 or knock-out of PV+ interneuron expression 24,25 are each sufficient to induce hippocampal hyperactivity. In MAM-treated rats, hippocampal hyperactivity leads to striatal hyperdopaminergia 21 , which is a core neurobiological feature of positive symptoms in schizophrenia 19 .…”