Erbb4 Deletion from Fast-Spiking Interneurons Causes Schizophrenia-like Phenotypes

Abstract

Genetic variation in neuregulin and its ErbB4 receptor has been linked to schizophrenia, although little is known about how they contribute to the disease process. Here, we have examined conditional Erbb4 mouse mutants to study how disruption of specific inhibitory circuits in the cerebral cortex may cause large-scale functional deficits. We found that deletion of ErbB4 from the two main classes of fast-spiking interneurons, chandelier and basket cells, causes relatively subtle but consistent synaptic defects. Surprisingly, these relatively small wiring abnormalities boost cortical excitability, increase oscillatory activity, and disrupt synchrony across cortical regions. These functional deficits are associated with increased locomotor activity, abnormal emotional responses, and impaired social behavior and cognitive function. Our results reinforce the view that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of schizophrenia.

Neuregulin-ERBB Signaling in the Nervous System and Neuropsychiatric Diseases

“…It promotes the formation and maturation of excitatory synapses on GABAergic interneurons, as quantified by PSD-95 and GluA1-positive puncta and mEPSC frequency (Abe et al, 2011; Del Pino et al, 2013; Ting et al, 2011) (Figure 3B, 3Ca). Erbb4 overexpression and inactivation in GAD65+ interneurons increases and decreases, respectively, the staining intensity of synaptophysin and vGlut1, both markers of excitatory axon terminals (Krivosheya et al, 2008).…”

“…Erbb4 overexpression and inactivation in GAD65+ interneurons increases and decreases, respectively, the staining intensity of synaptophysin and vGlut1, both markers of excitatory axon terminals (Krivosheya et al, 2008). In vivo genetic deletion of Erbb4 in interneurons (using Dlx5/6-Cre , PV-Cre , Lhx6-Cre mice) reduces mEPSC frequency and the density of vGlut-1+ terminals in PV+ interneurons of the hippocampus (Del Pino et al, 2013; Fazzari et al, 2010; Ting et al, 2011). However, in the medial prefrontal cortex, Erbb4 is required only for maturation, but not initial formation, of glutamatergic synapses on PV+ fast-spiking neurons in vivo (Yang et al, 2013b), perhaps reflecting a regional difference.…”

“…Chandelier cells lacking Erbb4 make fewer synapses onto the axon initial segments of pyramidal neurons of the hippocampus in vivo (Del Pino et al, 2013; Fazzari et al, 2010). Additionally, the density of interneuron axonal boutons of chandelier cells is increased by overexpressing Nrg1 Type III in pyramidal neurons (Fazzari et al, 2010).…”

Roles of Rac1 and Rac3 GTPases during the development of cortical and hippocampal GABAergic interneurons

“…Intriguingly, overexpression of kalirin-7 does not only increase the branching of dendrites of hippocampal CA1 interneurons, but induces also the formation of spine-like structures in these usually aspiny cells (Ma et al, 2008), indicating a role of this Rac GEF in potentiating the formation of excitatory postsynaptic terminals in GABAergic neurons. Interestingly, kalirin-7, NRG1, and ErbB4 are highly and specifically expressed in GABAergic interneurons, and have been associated with schizophrenia (Ma et al, 2001, 2005; Hill et al, 2006; Li et al, 2006; Fazzari et al, 2010; Del Pino et al, 2013; Kasnauskiene et al, 2013). Since the dendritic length of interneurons is reduced in schizophrenia (Kalus et al, 2002), understanding how NRG1/ErbB4 signaling regulates the dendrites of these cells may help clarifying the mechanisms underlying the cortical defects in this disorder.…”

Repeated Neonatal Sevoflurane Exposure-Induced Developmental Delays of Parvalbumin Interneurons and Cognitive Impairments Are Reversed by Environmental Enrichment

“…Abnormalities in PV interneurons are apparent in several neuropsychological diseases, including epilepsy [12], schizophrenia [13], Alzheimer's disease [14], and depression [15]. Disturbances in the functional maturation of PV interneurons during the peri-adolescent period may trigger the occurrence of schizophrenia, while maternal separation of male rats leads to a reduction of PV expression in the prefrontal cortex (PFC) and causes subsequent working memory impairments in adolescence [16].…”