Neuregulin 1 Prevents Phencyclidine-Induced Behavioral Impairments and Disruptions to GABAergic Signaling in Mice

Abstract

Background:Substantial evidence from human post-mortem and genetic studies has linked the neurotrophic factor neuregulin 1 (NRG1) to the pathophysiology of schizophrenia. Genetic animal models and in vitro experiments have suggested that altered NRG1 signaling, rather than protein changes, contributes to the symptomatology of schizophrenia. However, little is known about the effect of NRG1 on schizophrenia-relevant behavior and neurotransmission (particularly GABAergic and glutamatergic) in adult animals.Method:To address this question, we treated adult mice with the extracellular signaling domain of NRG1 and assessed spontaneous locomotor activity and acoustic startle response, as well as extracellular GABA, glutamate, and glycine levels in the prefrontal cortex and hippocampus via microdialysis. Furthermore, we asked whether the effect of NRG1 would differ under schizophrenia-relevant impairments in mice and therefore co-treated mice with NRG1 and phencyclidine (PCP) (3mg/kg).Results:Acute intraventricularly- or systemically-injected NRG1 did not affect spontaneous behavior, but prevented PCP induced hyperlocomotion and deficits of prepulse inhibition. NRG1 retrodialysis (10nM) reduced extracellular glutamate and glycine levels in the prefrontal cortex and hippocampus, and prevented PCP-induced increase in extracellular GABA levels in the hippocampus.Conclusion:With these results, we provide the first compelling in vivo evidence for the involvement of NRG1 signaling in schizophrenia-relevant behavior and neurotransmission in the adult nervous system, which highlight its treatment potential. Furthermore, the ability of NRG1 treatment to alter GABA, glutamate, and glycine levels in the presence of PCP also suggests that NRG1 signaling has the potential to alter disrupted neurotransmission in patients with schizophrenia.

Neuregulin-1 and schizophrenia in the genome-wide association study era

“…One study also suggests that excess Nrg1 may lead to similar impairments, as peak frequency, but not amplitude, of gamma oscillations were reduced in type I Nrg1 over-expressing mice (Deakin et al 2012), which also supports the inverted "U" model of Nrg1 function (Agarwal et al 2014;Law 2014;Talmage 2008). Gamma oscillations are linked to cognitive performance in humans (Engel et al 2015;Heermann et al 2011;Jensen et al 2007) and mice with abnormal Nrg1 expression which have the aforementioned deficits in evoked gamma oscillations, also have cognitive deficits (Agarwal et al 2014;Barz et al 2014;Chen et al 2008;Chesworth et al 2012;Duffy et al 2010;Yin et al 2013). Therefore, maladaptive gamma oscillations, putatively stemming from Nrg1-induced GABAergic dysfunction, may be a key downstream neurobiological consequence of abnormal Nrg1 expression, mediating risk for schizophrenia.…”

ErbB4 signaling in dopaminergic axonal projections increases extracellular dopamine levels and regulates spatial/working memory behaviors

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Figure 3 NRG/ErbB4 signaling increases extracellular DA levels by reducing DAT uptake efficiency. Experiments were performed in differentiated LUHMES cells, which exhibit numerous properties of DAergic neurons, 44 to determine if NRG/ErbB signaling cell-autonomously regulates extracellular DA levels. ( a ) Cells were treated for 30 min with either vehicle (V), 1 n m NRG1, or 10 μ m PD158780+1 n m NRG1 (PD+NRG1); DA levels in conditioned media are plotted as ratios of post- over pre-treatment values.

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“…Taken together, this evidence therefore suggests that NRG/ErbB signaling regulates homeostasis of extracellular DA levels either by directly modulating DAergic neurons, conceivably via mechanisms involving the DA transporter (DAT) or catechol- O -methyltransferase, by indirectly modulating neuronal circuits through GABAergic interneurons, 44 or both. The major aims of the present study were to determine if and how ErbB4 signaling in mesencephalic DAergic neurons is necessary to acutely regulate extracellular DA levels, and to determine if chronic ErbB4 ablation in monoaminergic neurons affects behaviors relevant to psychiatric disorders.…”

Repair Injured Heart by Regulating Cardiac Regenerative Signals

“…Indeed, NRG1 has shown the essential role in controlling rapid impulse conduction in the central nervous system through determining the myelination of an individual axon [ 27 ], and the disorders in NRG1-ErbB signaling have been etiologically implicated in schizophrenia [ 28 ], Parkinson's disease [ 29 ], Alzheimer's disease [ 30 ], and Hirschsprung disease [ 31 ]. Importantly, administration of NRG1 displayed protective effects in experimental model of neuron injury [ 32 ], and this trophic factor can significantly attenuate cognitive function and improve behavioral performance [ 33 ].…”