11 July 2011. Altering dopamine signaling in one region of the brain can have substantial repercussions elsewhere, according to a study published online on July 5, 2011, in the Proceedings of the National Academy of Sciences. The laboratories of Wen-Ju Gao at Drexel University in Philadelphia, Pennsylvania, and Eric Kandel at Columbia University in New York joined forces to examine the synaptic consequences of overexpressing D2 dopamine receptors in the striatum of mice. They turned up a deficit in GABAergic transmission in the prefrontal cortex—a result that links two disparate findings in schizophrenia and suggests that impaired cognition stems from overactive dopamine signaling in the striatum.
The work explores the synaptic repercussions in mice engineered to overexpress D2 receptors specifically in the striatum, as found in schizophrenia. This mouse model debuted in 2006 with a study that found cognitive and motivational deficits in these D2 receptor-overexpressing (D2R-OE) mice (see SRF related news story). This suggested that hyperactive dopamine signaling—widely viewed as causing psychosis—may also spur the cognitive and negative symptoms of schizophrenia (Simpson et al., 2010). The new study adds heft to this idea by finding decreased GABAergic signaling in the prefrontal cortex, a region important for cognition and which also shows decreases in GABA-related molecules in postmortem studies of schizophrenia.
Turning down inhibition from afar
Because D2R-OE mice show deficits in prefrontal cortex-dependent tasks, including those measuring working memory and incentive motivation (see SRF related news story), first author Yan-Chun Li and colleagues made brain slices of the medial prefrontal cortex. Using whole-cell patch clamp recordings to detect the currents impinging upon layer V pyramidal neurons, the researchers found that spontaneously occurring inhibitory post-synaptic currents (sIPSCs) in D2R-OE mice occurred half as often and were about half the size of those recorded in control littermates. These changes were not accompanied by frequency or amplitude differences in miniature IPSCs (mIPSCs), which reflect the state of the pre-synaptic vesicle release machinery or post-synaptic receptors, respectively. The inherent excitability of layer V pyramidal cells was also unchanged in D2R-OE mice. Together, these results point to a suppression of inhibitory signals in the medial PFC in D2R-OE mice.
In contrast, the researchers found evidence for enhanced excitatory neurotransmission. The spontaneously occurring excitatory post-synaptic currents (sEPSCs) in D2R-OE mice occurred about twice as frequently as those in control littermates, though they were the same size, and no difference in mEPSCs was detected.
Blunted sensitivity to dopamine
The PFC receives some of the far-reaching dopamine projections of the brain, and previous studies have found that dopamine can modulate inhibitory synaptic transmission there. This prompted the researchers to check whether the subdued inhibitory transmission found in D2R-OE mice would be similarly sensitive to dopamine. The results, though complicated, suggest that the inhibitory signals are somewhat impervious to dopamine. In control mice, the lowest concentration of dopamine increased the size of IPSCs evoked by stimulating the neuron's synaptic inputs, whereas two higher concentrations decreased IPSC size. This pattern was not matched in D2R-OE mice: the lowest concentration of dopamine had no effect on IPSC size, whereas a higher effect increased IPSC size, and the highest concentration had no effect.
Further experiments explored whether D1 or D2 receptors were behind this change in dopamine sensitivity. While a D1 receptor agonist similarly modulated IPSCs in both kinds of mice, a D2 receptor agonist decreased the IPSC size in controls only, and was ineffective in D2R-OE mice. This suggests that, in addition to a decrease in inhibitory synaptic transmission in the PFC, these inhibitory signals are not as open to modulation, both of which could contribute to cognitive defects.
Explaining action at a distance
These abnormalities in the PFC could reflect a developmental program gone awry as a result of too many D2Rs in the striatum. Alternatively, it could stem from aberrant striatal signaling in adulthood, which could influence signaling in the PFC through a network of connections. To get at this, the researchers removed the extra D2 receptors in young adult animals by feeding them doxycycline for two weeks, which turned off the promoter driving D2R overexpression. This reversed the synaptic signal changes in D2R-OE mice, which had both spontaneous IPSCs and EPSCs that were no different from controls. This argues that aberrant dopamine signaling in the striatum reverberates throughout a mature network of connections in the brain to influence signaling in the PFC.
Similarly, the motivation deficits found in D2R-OE mice reverse upon doxycycline treatment; however, the working memory and conditional associative learning do not. This suggests that the synaptic changes documented here in the PFC may contribute more to the motivation deficits and less to the cognitive impairments found in these animals.
The authors note at least two ways by which D2R overexpression in the striatum may alter PFC function. Altered activity in the striatum could result in altered activity in the PFC via a domino effect through a pathway traveling from the striatum, to the pallidum (the basal ganglia output), to the thalamus, and then to the cortex. Alternatively, D2R overexpression in the striatum could alter dopamine release in the PFC via dopamine-containing ventral tegmental neurons, which receive striatal inputs. However it happens, the results illustrate the far-reaching effects of a fairly specific manipulation, and suggest that the cognitive and negative symptoms of schizophrenia may stem from a primary defect in the striatum, rather than the cortex.—Michele Solis.
Li YC, Kellendonk C, Simpson EH, Kandel ER, Gao WJ. D2 receptor overexpression in the striatum leads to a deficit in inhibitory transmission and dopamine sensitivity in mouse prefrontal cortex. Proc Natl Acad Sci U S A. 2011 Jul 5.