The Importance of the NRG-1/ErbB4 Pathway for Synaptic Plasticity and Behaviors Associated with Psychiatric Disorders

Abstract

Neuregulin 1 (NRG-1) and its receptor ErbB4 have emerged as biologically plausible schizophrenia risk factors, modulators of GABAergic and dopaminergic neurotransmission, and as potent regulators of glutamatergic synaptic plasticity. NRG-1 acutely depotentiates LTP in hippocampal slices, and blocking ErbB kinase activity inhibits LTP reversal by theta pulse stimuli (TPS), an activity-dependent reversal paradigm. NRG-1/ErbB4 signaling in parvalbumin (PV) interneurons has been implicated in inhibitory transmission onto pyramidal neurons. However, the role of ErbB4, in particular in PV interneurons, for LTP reversal has not been investigated. Here we show that ErbB4 null (ErbB4-/-) and PV interneuron-restricted mutant (PV-Cre;ErbB4) mice, as well as NRG-1 hypomorphic mice, exhibit increased hippocampal LTP. Moreover, both ErbB4-/- and PV-Cre;ErbB4 mice lack TPS-mediated LTP reversal. A comparative behavioral analysis of full and conditional ErbB4 mutant mice revealed that both exhibit hyperactivity in a novel environment and deficits in pre-pulse inhibition of the startle response. Strikingly, however, only ErbB4-/- mice exhibit reduced anxiety-like behaviors in the elevated plus maze task and deficits in cued and contextual fear conditioning. These results suggest that aberrant NRG-1/ErbB4 signaling in PV interneurons accounts for some but not all behavioral abnormalities observed in ErbB4-/- mice. Consistent with the observation that PV-Cre;ErbB4 mice exhibit normal fear conditioning, we find that ErbB4 is broadly expressed in the amygdala, largely by cells negative for PV. These findings are important to better understand ErbB4's role in complex behaviors and warrant further analysis of ErbB4 mutant mice lacking the receptor in distinct neuron types.

Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors

“…These results suggest that alterations in D4R function may underlie endophenotypes shared by both disorders. Importantly, mice harboring targeted mutations of NRG-1 and ErbB4 exhibit behavioral deficits (including working memory) similar to other rodent models for schizophrenia (37,38), and NRG-1 hypomorphs respond positively to clozapine administration (37), suggesting that D4R modulation underlies these behaviors. Pharmacological and genetic studies targeting D4Rs in primates and rodents also support a critical role of the receptor in cognitive processes (36,39,40).…”

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…Genomic ERBB4 deletion was accompanied by a B30% reduction in the number of PV þ interneurons and lead to decreased oscillatory activity (Fisahn et al, 2009), whereas conditional deletion in postmitotic interneurons, albeit with residual expression due to low receptor turnover, displayed normal PV þ cell numbers and lead to increased oscillatory power (Del Pino et al, 2013), suggesting that reduced gamma oscillations in schizophrenia might arise from insults very early in development. Despite the evidence in favor of a common NRG1/ErbB4 signaling/PV þ interneuron dysfunction phenotype, restricting ERBB4 deletion to PV þ interneurons did not account for all of the NRG1/ErbB4-associated behavioral abnormalities due to the presence of a large number of NRG1 þ /PV À cells in the amygdala (Shamir et al, 2012). This contrast is a quintessential example of how similar genetic insults lead to divergent phenotypes depending on their developmental timing and cell type-specific expression, as well as brain regionspecific differences, and highlights the importance of GABAergic cell type-specific effects of genetic manipulations.…”

ErbB4 reduces synaptic GABA A currents independent of its receptor tyrosine kinase activity

“…Four-to 6-wk-old Sprague-Dawley rats were transcardially perfused with 4% paraformaldehyde (PFA) in 0.1 M PBS (pH 7.4). Brains were postfixed overnight in the same fixative, and 50-μm free-floating sections were stained and analyzed as described (9,10). All animal protocols were approved by National Institute of Child Health and Human Development (NICHD) Animal Care and Use Committee.…”

“…In the neocortex and hippocampus of rodents, monkeys, and humans, ErbB4 expression is restricted to GABAergic interneurons, and its expression is particularly high in parvalbumin-positive fastspiking (PV+) interneurons (8,9). Of note, targeted ablation of ErbB4 specifically in PV+ interneurons recapitulates behavioral abnormalities of full ErbB4-null mice, highlighting the importance of ErbB4 signaling in this GABAergic interneuron subclass (10). Moreover, gamma oscillations, a type of high-frequency network activity that depends on synchronization of local circuits by PV+ interneurons, are augmented by Neuregulin (NRG)1 in vitro in an ErbB4-dependent manner (11).…”