Neuregulin-1 regulates LTP at CA1 hippocampal synapses through activation of dopamine D4 receptors

Abstract

Neuregulin-1 (NRG-1) is genetically linked with schizophrenia, a neurodevelopmental cognitive disorder characterized by imbalances in glutamatergic and dopaminergic function. NRG-1 regulates numerous neurodevelopmental processes and, in the adult, suppresses or reverses long-term potentiation (LTP) at hippocampal glutamatergic synapses. Here we show that NRG-1 stimulates dopamine release in the hippocampus and reverses early-phase LTP via activation of D4 dopamine receptors (D4R). NRG-1 fails to depotentiate LTP in hippocampal slices treated with the antipsychotic clozapine and other more selective D4R antagonists. Moreover, LTP is not depotentiated in D4R null mice by either NRG-1 or theta-pulse stimuli. Conversely, direct D4R activation mimics NRG-1 and reduces AMPA receptor currents and surface expression. These findings demonstrate that NRG-1 mediates its unique role in counteracting LTP via dopamine signaling and opens future directions to study new aspects of NRG function. The novel functional link between NRG-1, dopamine, and glutamate has important implications for understanding how imbalances in Neuregulin-ErbB signaling can impinge on dopaminergic and glutamatergic function, neurotransmitter pathways associated with schizophrenia.depotentiation ͉ ErbB receptor ͉ plasticity ͉ schizophrenia ͉ clozapine T he trophic and differentiation factor NRG-1 and its receptors (ErbB2-4) are expressed in the developing nervous system and adult brain, including the hippocampus. NRG-1 is translated as a transmembrane protein and released in an activity-dependent manner (1). Initially, long-term NRG-1 signaling was shown to regulate neuronal expression of neurotransmitter receptor genes for glutamate, acetylcholine, and GABA (2-5). More recently, the tight association of the NRG-1 receptor ErbB4 with glutamate receptors at postsynaptic densities suggested that NRG-1 signaling could regulate synaptic function in a more acute fashion (6, 7). Consistent with this idea, we and others have shown that NRG-1␤ rapidly regulates glutamatergic (7-11) and cholinergic (12) synaptic function in the hippocampus and prefrontal cortex (PFC).Long term potentiation (LTP) and long term depression (LTD) at Schaeffer collateral-to-CA1 hippocampal synapses (SC-CA1) are believed to underlie complex cognitive processes such as learning and memory. At this synapse, postsynaptic NMDAR activation and increases in AMPAR excitatory postsynaptic currents (EPSCs) are necessary for LTP induction and expression, respectively. An additional mechanism that contributes to synaptic homeostasis at adult glutamatergic synapses is depotentiation (13,14). In acute hippocampal slices and in freely moving animals, LTP is reversed (depotentiated) by brief, subthreshold theta pulse stimulation (TPS) if delivered during a labile period shortly after LTP induction (14). In the amygdala, depotentiation correlates with fear extinction and requires AMPAR internalization (15). We recently reported that NRG-1␤ depotentiates early-phase LTP at hippocampal SC-CA1 synapses,...

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

“…Pharmacological and genetic studies targeting D4Rs in primates and rodents also support a critical role of the receptor in cognitive processes (36,39,40). Therefore, our prior (18) and present studies on the importance of the NRG/ErbB and D4R signaling for synaptic plasticity and γ oscillations, respectively, suggest that functional interactions between both signaling pathways may be critically important for cognitive functions.…”

“…Both signaling pathways acutely regulate NMDA and AMPA receptor trafficking (18,32), and ErbB4Rs are closely associated with glutamatergic synapses on PV+ interneurons (17). Even though NMDA and AMPA receptors are not necessary for some types of γ oscillations (8), γ power can be increased through regulation of AMPA and/or NMDA receptors in PV+ interneurons by modulating excitatory/inhibitory balance and optimizing phase-synchronization of action potential discharges (31).…”

“…The important association of γ oscillations with attention, working memory, and other cognitive functions (1), and their perturbation in numerous psychiatric disorders (2,3,42,43), underscores the potential therapeutic value of targeting networks that generate and regulate γ oscillations. We propose, on the basis of the functional properties and expression of ErbB4 and D4Rs in PV+ interneurons in the dorsal lateral prefrontal cortex (21,25) and hippocampus (this study), as well as their effects on KA-induced γ oscillations and plasticity (18,19), that these receptors are well situated to modulate network activity that impacts cognition. The fact that D4R-specific antagonists were found to be ineffective as antipsychotics for the treatment of schizophrenia (44,45) does not negate the potential use of D4R targeting drugs to treat cognitive deficits, as suggested by studies in primates and rodents (39,40,46,47).…”

“…The rodent frontal cortex and hippocampus receive sparse dopaminergic innervation from the ventral tegmental area that regulates synaptic transmission and plasticity (16). We recently found that signaling via neuregulin-1 (NRG-1) and its cognate transmembrane receptor ErbB4, both genetically associated with increased risk for schizophrenia (17), dramatically increases extracellular DA levels and regulates hippocampal synaptic plasticity via DA D4 receptor (D4R) activation (18). We also reported that NRG-1/ErbB4 signaling greatly augments the power of KA-induced γ oscillations in acute hippocampal slices (19).…”

Neuregulin links dopaminergic and glutamatergic neurotransmission to control hippocampal synaptic plasticity

“…7 These new findings position the NRG-1/ErbB4 signaling pathway at the crossroads between dopaminergic and glutamatergic neurotransmission and offer novel ways to consolidate genetic, functional and pharmacological data toward a better understanding of the etiological processes underlying schizophrenia, and the role of NRG-1 for normal synaptic function and plasticity. The currently available data suggest that hippocampal interneurons might play a crucial role in mediating NRG-1 induced depotentiation.…”