Type III Neuregulin 1 Is Required for Multiple Forms of Excitatory Synaptic Plasticity of Mouse Cortico-Amygdala Circuits

Abstract

The amygdala plays an important role in the formation and storage of memories associated with emotional events. The cortical glutamatergic inputs onto pyramidal neurons in the basolateral nucleus of the amygdala (BLA) contribute to this process. As the interaction between neuregulin 1 (Nrg1) and its ErbB receptors has been implicated in the pathological mechanisms of schizophrenia, loss of Nrg1 may disrupt cortical-amygdala neural circuits, resulting in altered processing of salient memories. Here we show that Nrg1 is critical in multiple forms of plasticity of cortical projections to pyramidal neurons of the BLA. The miniature EPSCs in Nrg1 heterozygous animals have a faster time constant of decay and evoked synaptic currents have a smaller NMDA/AMPA ratio than those recorded in wild-type (WT) littermates. Both high-frequency electrical stimulation of cortical inputs and burst stimulation combined with nicotine exposure results in long-lasting potentiation in WT animals. However, the same manipulations have little to no effect on glutamatergic synaptic plasticity in the BLA from Nrg1 heterozygous mice. Comparison of WT, Nrg1 heterozygous animals and ␣7 nicotinic receptor heterozygous mice reveals that the sustained phase of potentiation of glutamatergic transmission after burst stimulation with or without nicotine only occurs in the WT mice. Together, these findings support the idea that type III Nrg1 is essential to multiple aspects of the modulation of excitatory plasticity at cortical-BLA synapses.

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

“…In another study, type III Nrg1 heterozygote "knockout" mice showed a faster time constant of decay, but no change in amplitude or frequency, of mEPSCs in amygdala compared with wild-type (WT) mice (Jiang et al 2013). Type III Nrg1 hypomorphs also had lower AMPA/NMDA ratios, indicative of LTP and neural plasticity, in response to evoked electrical currents compared to WT (Jiang et al 2013). Similarly, type I (Yin et al 2013), but not type III (Agarwal et al 2014), Nrg1 over-expressing mice showed reduced m/sEPSC in prefrontal cortex and hippocampus, and both type I/III Nrg1 overexpressing mice showed impaired synaptic plasticity in the hippocampus, demonstrated by a downward shift in the input-output curve (Agarwal et al 2014;Yin et al 2013).…”

“…In Nrg1 hypomorphic rodents, miniature and spontaneous excitatory post synaptic currents (m/sEPSC) were decreased in the CA1 subregion of the hippocampus (Agarwal et al 2014), but long-term potentiation (LTP) appeared normal according to input-output curves at Schaffer collateral-CA1 synapses in the hippocampus (Agarwal et al 2014). In another study, type III Nrg1 heterozygote "knockout" mice showed a faster time constant of decay, but no change in amplitude or frequency, of mEPSCs in amygdala compared with wild-type (WT) mice (Jiang et al 2013). Type III Nrg1 hypomorphs also had lower AMPA/NMDA ratios, indicative of LTP and neural plasticity, in response to evoked electrical currents compared to WT (Jiang et al 2013).…”

Neuregulin-ERBB Signaling in the Nervous System and Neuropsychiatric Diseases

“…This plasticity is impaired in Nrg1 Type III heterozygous mice (Jiang et al, 2013). Here Nrg1 Type III is believed to target nicotinc α7 AChR to the presynaptic terminal in cortical projection neurons (Hancock et al, 2008; Zhong et al, 2008) and thus modulate excitatory plasticity at cortical-amygdala synapses (Chen et al, 2008; Jiang et al, 2013) (Figure 6Cd). In slices, the addition of soluble Erbb4-ECD partially rescues LTP deficits although it is unclear whether the backward signaling is via interaction with Erbb4 on interneurons or through some other mechanism or both.…”

Multiple Nicotinic Acetylcholine Receptor Subtypes in the Mouse Amygdala Regulate Affective Behaviors and Response to Social Stress

“…The non-competitive, non-selective antagonist mecamylamine and the partial agonist cytisine are both effective in mouse models of antidepressant efficacy and converge to decrease neuronal activity in the basolateral amygdala (BLA) (Mineur et al, 2007), a brain region that is often hyperactivated in depressed patients (Drevets et al, 2008). In addition, nicotine can facilitate glutamatergic signaling in the amygdala through activity of α7 nAChRs (Jiang and Role, 2008) and these nAChRs are particularly critical for synaptic plasticity in this brain region (Jiang et al, 2013). Although many nAChR subtypes may contribute to anxiety-and depression-like behaviors, based on the critical role of the amygdala in emotional behaviors, the current study investigated whether altering cholinergic signaling through β2* or α7 nAChRs in the amygdala could affect neuronal activity and performance in behaviors related to stress and depression.…”