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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.

SUBMITTER: Kwon OB

PROVIDER: S-EPMC2563131 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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

Kwon Oh Bin OB Paredes Daniel D Gonzalez Carmen M CM Neddens Jörg J Hernandez Luis L Vullhorst Detlef D Buonanno Andres A

Proceedings of the National Academy of Sciences of the United States of America 20081001 40

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 ...[more]

PMID: 18832154

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Project description:It is well established that selective activation of group I metabotropic glutamate (mGlu) receptors induces LTD of synaptic transmission at Schaffer collateral-CA1 synapses. In contrast, application of 1S,3R-ACPD, a mixed agonist at group I and group II mGlu receptors, induces LTP. Using whole-cell recordings from CA1 pyramidal cells and field recordings in the hippocampal CA1 region, we investigated the specific contribution of group II mGlu receptors to synaptic plasticity at Schaffer collateral-CA1 synapses in acute slices of adult mice. Pharmacological activation of group II mGlu receptors (mGlu2 and mGlu3 receptors) with the specific agonist LY354740 in conjunction with electrical stimulation induced postsynaptic LTP. This form of plasticity requires coactivation of NMDA receptors (NMDARs). Group II mGlu receptor activation led to PKC-dependent phosphorylation of the GluN1 subunit. We found that both synaptic and extrasynaptic NMDARs, which are differentially modulated by mGlu2 and mGlu3 receptors, contribute to LTP induction. Furthermore, LTP initiated by activation of group II mGlu receptors was not occluded by LTP induced with high-frequency trains of stimuli. However, the phosphorylation of NMDARs mediated by group II mGlu receptor activation led to a priming effect that enhanced subsequent high-frequency stimulation-induced LTP. These findings reveal a novel metaplastic mechanism through which group II mGlu receptors modulate synaptic function at the Schaffer collateral input to CA1 pyramidal cells, thereby lowering the threshold to induce plasticity.Significance statementThe group II metabotropic glutamate (mGlu II) receptors exert a well characterized action on presynaptic neuron terminals to modulate neurotransmitter release. Here, we show that these receptors also have postsynaptic effects in promoting the induction of synaptic plasticity. Using an electrophysiological approach including field and whole-cell patch recording in hippocampi from wild-type and transgenic mice, we show that activation of group II mGlu receptors enhances NMDA receptor (NMDAR)-mediated currents through PKC-dependent phosphorylation. This priming of NMDARs lowers the threshold for the induction of LTP of synaptic transmission. These findings may also provide new insights into the mechanisms through which drugs targeting mGlu II receptors alleviate hypoglutamatergic conditions such as those occurring in certain brain disorders such as schizophrenia.

Dataset Information

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

Publications

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

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