Genetic evidence for the bidirectional modulation of synaptic plasticity in the prefrontal cortex by D1 receptors

Abstract

To address the role of D1 receptors in the medial prefrontal cortex, we combined pharmacological and genetic manipulations to examine long-term synaptic potentiation (LTP)͞long-term synaptic depression (LTD) in brain slices of rats and mice. We found that the D1 antagonist SCH23390 selectively blocked the maintenance but not the induction of LTP in the prefrontal cortex. Conversely, activation of D1 receptors facilitated the maintenance of LTP, and this effect is impaired in heterozygous D1 receptor knockout mice. Low-frequency stimulation induced a transient depression in the medial prefrontal cortex. This depression could be transformed into LTD by coapplication of dopamine. Coapplication of dopamine, however, shows no facilitating effect on LTD in heterozygous D1 receptor knockout mice. These results provide pharmacological and genetic evidence for a role of D1 receptors in the bidirectional modulation of synaptic plasticity in the medial prefrontal cortex. The absence of this modulation in heterozygous knockout mice shows that a dysregulation of dopamine receptor expression levels can have dramatic effects on synaptic plasticity in the prefrontal cortex.T he prefrontal cortex is thought to be the highest association area in the mammalian cortex and is required for proper executive control. In primates the dorsolateral prefrontal cortex, alone, has been implicated in several different, partly overlapping, cognitive processes, including inhibitory control, working memory, selective attention, attentional-set shifting, rule learning, and strategy switching. In rodents, where the architecture of the cortex is simpler than that of primates, the medial prefrontal cortex (mPFC), the cortex that encompasses the infralimbic and prelimbic areas, is considered to be homologous to the primate dorsolateral prefrontal cortex (1, 2).Consistent with this homology, a variety of studies have shown that dopamine modulates neuronal activity in the prefrontal cortex and affects working memory, attentional performance, attentional-set shifting, and strategy switching (3-9). Some functions of mPFC, such as strategy shifting or rule learning, may be affected by dopaminergic modulation of long-term synaptic plasticity. Dopamine indeed affects long-term plasticity in the prefrontal cortex. It facilitates long-term synaptic depression (LTD) via D1 and D2 receptors (10, 11), and D1 activation has been shown to be required for N-methyl-D-aspartate (NMDA) receptor-dependent long-term synaptic potentiation (LTP) at hippocampal-prefrontal cortex synapses (12).To further our understanding of how dopamine modulates long-term synaptic plasticity in opposite directions, and to develop a model for exploring the underlying molecular signaling pathways, we examined LTP and LTD in slices of the mPFC from rats, wild-type mice, and heterozygous dopamine D1 receptor knockout mice. Heterozygous D1 receptor knockout mice show a 50% reduction in receptor number. They allow us to address specifically the function of the D1 receptor as opposed to both D1 ...

Consolidation of learning strategies during spatial working memory task requires protein synthesis in the prefrontal cortex

“…This finding is consistent with the idea that learning of strategies required to solve complex problems, such as the DNMTP task with retroactive interference, may have a long-lasting memory component that shares the cellular and molecular properties of other well studied long-term memory processes, i.e., gene expression and protein synthesis (4,31,32). In a recent paper, Huang et al (33) reported that long-term potentiation (LTP) can occur in the rat mPFC by applying repeated tetanizations to slice preparations and that this LTP is blocked by ANI. Our data further demonstrate that consolidation of learning strategies in the DNMTP task with retroactive interference requires protein synthesis and that the mPFC is a critical site for this learning-induced de novo proteins.…”

Chronic cannabinoid administration in vivo compromises extinction of fear memory

“…In five neurons tested, the input resistance (R in ) of IL neurons from vehiclepretreated rats was 298.9 ‫ע‬ 23.7 M⍀ (n = 5), which was not different from that of vehicle-pretreated rats (295.0 ‫ע‬ 18.2 M⍀, n = 5, P > 0.1). Orthodromic stimuli applied to the layer II of rat prefrontal cortex slices elicited excitatory postsynaptic currents (EPSCs) in layer V (Huang et al 2004). Bath application of the AMPA receptor antagonist CNQX (10 µM) plus the NMDA receptor antagonist D-APV (50 µM) blocked the EPSCs, revealing an IPSC that was completely blocked by bicuculline (10 µM), confirming the mediation by GABA A receptors (Fig.…”

Dopaminergic signaling in dendritic spines

“…In addition, activation of D1-class receptors lowered the threshold for both LTP and LTD at CA1 synapses in vivo [62]. Similarly, in deep layer PFC synapses and hippocampal-PFC synapses, agonists of D1-class receptors facilitated, whereas antagonists impaired, NMDAR-dependent LTP via cAMP-dependent mechanisms [63][64]. Acting at both D1-and D2-class receptors, DA at high concentrations facilitates LTD, whereas at low concentrations promotes LTP [65].…”

“…In the nucleus accumbens, most studies report that DA attenuates corticoaccumbal glutamatergic input by acting on D1-class receptors [6]. This attenuation, according to one proposed mechanism, is mediated by an inhibitory feedback action of adenosine, liberated following facilitation of NMDARs by D1-mediated PKC activation in postsynaptic neurons [58] layer PFC synapses and hippocampal-PFC synapses, agonists of D1-class receptors facilitated, whereas antagonists impaired, NMDAR-dependent LTP via cAMP-dependent mechanisms [63][64]. Acting at both D1-and D2-class receptors, DA at high concentrations facilitates LTD, whereas at low concentrations promotes LTP [65].…”