Dopamine (DA) plays crucial roles in the cognitive functioning of the
prefrontal cortex (PFC), which, to a large degree, depends on lasting
neural traces formed in
prefrontal networks. The establishment of these
permanent traces requires changes in cortical
synaptic efficacy. DA, via the D(1)-class receptors, is thought to gate or facilitate
synaptic plasticity in the PFC, with little role recognized for the D(2)-class receptors. Here we show that, when significantly elevated, DA erodes, rather than facilitates, the induction of
long-term potentiation (LTP) in the PFC by acting at the far less abundant cortical D(2)-class receptors through a dominant coupling to the
protein phosphatase 1 (PP1) activity in
postsynaptic neurons. In
mice with persistently elevated
extracellular DA, resulting from inactivation of the DA transporter (DAT) gene, LTP in layer V PFC
pyramidal neurons cannot be established, regardless of induction protocols. Acute increase of
dopaminergic transmission by DAT blockers or overstimulation of D(2) receptors in normal
mice have similar LTP shutoff effects. LTP in
mutant mice can be rescued by a single in vivo administration of D(2)-class antagonists. Suppression of
postsynaptic PP1
mimics and occludes the D(2)-mediated rescue of LTP in
mutant mice and prevents the acute erosion of LTP by D(2)
agonists in normal
mice. Our studies reveal a mechanistically unique
heterosynaptic PP1 gate that is constitutively driven by background DA to influence
LTP induction. By blocking
prefrontal synaptic plasticity, excessive DA may prevent storage of lasting
memory traces in PFC networks and impair
executive functions.
