Depotentiating via Dopamine

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Science  07 Nov 2008:
Vol. 322, Issue 5903, pp. 825
DOI: 10.1126/science.322.5903.825a

The capacity to associate events, in a neuronal context, is thought to rely on long-term potentiation (LTP), a mechanism that strengthens glutamatergic (excitatory) synaptic connections. Strong novel stimuli can selectively reverse or overwrite LTP by a mechanism known as depotentiation, which is thought to keep synapses from becoming saturated and thereby to maintain them in a dynamically responsive range. Neuregulin-1 is a factor expressed in brain and can effectively depotentiate LTP in the hippocampus. Kwon et al. found that neuregulin depotentiates LTP by recruiting a dopaminergic signaling pathway involving the dopamine D4 receptor (D4R), which is a target of the antipsychotic clozapine. Neuregulin acutely triggers dopamine release in the hippocampus, which in turn depotentiates LTP by activating D4Rs. The direct activation of D4Rs by selective agonists mimics the action of neuregulin in removing AMPA-type glutamate receptors from synapses. Mutant mice lacking D4Rs fail to depotentiate LTP in response either to neuregulin or to electrical stimuli. These observations thus functionally associate three signaling pathways (dopamine, glutamate, and neuregulin) in the regulation of synaptic plasticity. — PRS

Proc. Natl. Acad. Sci. U.S.A. 105, 15587 (2008).

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