Abstract
The prefrontal cortex (PFC), a key brain region for cognitive and emotional processes, is highly regulated by dopaminergic inputs. The dopamine D4 receptor, which is enriched in PFC, has been implicated in mental disorders, such as attention deficit-hyperactivity disorder and schizophrenia. Recently we have found homeostatic regulation of AMPA receptor-mediated synaptic transmission in PFC pyramidal neurons by the D4 receptor, providing a potential mechanism for D4 in stabilizing cortical excitability. Because stress is tightly linked to adaptive and maladaptive changes associated with mental health and disorders, we examined the synaptic actions of D4 in stressed rats. We found that neural excitability was elevated by acute stress and dampened by repeated stress. D4 activation produced a potent reduction of excitatory transmission in acutely stressed animals and a marked increase of excitatory transmission in repeatedly stressed animals. These effects of D4 targeted GluA2-lacking AMPA receptors and relied on the bi-directional regulation of calcium/calmodulin kinase II activity. The restoration of PFC glutamatergic transmission in stress conditions may enable D4 receptors to serve as a synaptic stabilizer in normal and pathological conditions.
Highlights
The dopamine D4 receptors in prefrontal cortex (PFC) play a key role in mental health and disorders
A significant reduction in the firing rate was observed in repeatedly stressed (RS) animals (Fig. 1B, NS: 1.25 Ϯ 0.41 Hz, n ϭ 8; RS: 0.37 Ϯ 0.10 Hz, n ϭ 11, p Ͻ 0.01, t test). These data indicate that the excitability of PFC pyramidal neurons is elevated by acute stress and dampened by chronic stress
We examined the impact of D4 receptor activation on the excitability of PFC pyramidal neurons from stressed animals
Summary
The dopamine D4 receptors in prefrontal cortex (PFC) play a key role in mental health and disorders. We have found homeostatic regulation of AMPA receptor-mediated synaptic transmission in PFC pyramidal neurons by the D4 receptor, providing a potential mechanism for D4 in stabilizing cortical excitability. We have demonstrated that D4 stimulation causes a profound depression of AMPA receptor (AMPAR) responses in PFC pyramidal neurons when their activity is elevated in vitro and causes a marked potentiation of AMPAR responses when their activity is dampened in vitro [23, 24]. It suggests that D4 receptors may use the homeostatic control of glutamatergic transmission to stabilize the activity of PFC circuits. Knowledge gained from this study should help us understand the role of D4 in the adaptive and maladaptive changes linked to stress
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