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Target Potassium Channels for Schizophrenia Symptoms?

7 March 2012. Adding extra dopamine receptors to the striatum—a state that models the hypothesized hyperdopaminergic state in schizophrenia—can substantially remodel adult neurons there, according to a study in mice published February 15 in the Journal of Neuroscience. An overabundance of dopamine 2 (D2) receptors shrank dendrites and increased excitability in striatal neurons, but not beyond repair. These changes were mediated by workaday potassium channels, and the concomitant motivational deficits in these mice suggest a new target for treating negative symptoms of schizophrenia.

Led by Christoph Kellendonk at Columbia University in New York, the study is the latest installment of findings from their dopamine 2 receptor overexpressing (D2R-OE) mice, which mimic the extra D2 receptors that have been found in the striatum in postmortem and brain imaging studies of schizophrenia (Davis et al., 1991; Abi-Dargham et al., 2000). Debuted in 2006, these mice exhibit both cognitive and motivational deficits, suggesting that hyperactive dopamine signaling may go beyond its widely accepted role in psychosis (see SRF related news story). In seeking the neurobiological basis for these behavioral abnormalities, Kellendonk and his team have found deficient GABAergic signaling in the prefrontal cortex—something that indicates that boosted dopamine signaling in the striatum can have far-reaching consequences in the brain (see SRF related news story). The new study stays closer to home to explore the consequences for striatal neurons themselves, namely, the medium spiny neurons (MSNs) that form the striatum’s output.

Readily reversible
First author Maxime Cazorla and colleagues focused on the shape and physiology of MSNs in D2R-OE adult mice at one month, three months, or nine months old. Overall, volume of the striatum—95 percent of its neurons being MSNs—was decreased by about 30 percent in these mice, compared to control littermates, or to mice carrying but not expressing the D2R transgene. The MSNs themselves had shorter dendrites and fewer branches—up to a third less in both cases—than those in controls, though the number of dendrites exiting the cell body did not differ.

To probe the function of these MSNs, the researchers made whole-cell patch-clamp recordings in brain slices of the striatum. There, the researchers documented increases in the excitability of MSNs in D2R-OE mice: the neurons had a higher resting potential, a higher input resistance, and fired more action potentials in response to a fixed current injection. These changes were observed in both the D2R-expressing and D1R-expressing subtypes of MSNs, which suggests that D2R overexpression can alter excitability of neurons that don’t themselves contain D2Rs, maybe through some network-mediated means.

Restoring D2R expression to normal levels by feeding mice doxycycline to turn off the transgene for two weeks resulted in dendritic morphology and neuron excitability that did not differ from controls. Though dendrite branching seemed normal enough in this experiment, striatal volume was halfway between the shrunken state found in D2R-OE mice and the plump size in controls. Still, these changes point to dynamic responses of MSNs to D2R expression levels, even in adulthood.

Pivotal potassium channels
The increased excitability raised the possibility that potassium channels had been altered in D2R-OE mice. Because the inwardly rectifying potassium current contributes to the hyperpolarized membrane potential of MSNs, the researchers measured the current using voltage clamp. They found it was substantially dampened in D2R-OE mice in both D2R- and D1R-expressing MSNs, amounting to about half the current measured in controls. Immunoblotting with antibodies to the two main channels responsible for the inward rectifier current, Kir2.1 and Kir2.3, revealed half the control levels of both proteins in D2R-OE mice. A decrease in Kir2.3 mRNA was also found in D2R-OE mice.

The researchers then connected these potassium channels to MSN morphology and excitability. Knocking down Kir2 with a dominant-negative mutant in the striatum was sufficient to produce dendrite atrophy and hyperexcitability in control animals that looked very similar to that observed in D2R-OE mice. This suggests that alterations to potassium channels spur the structural and physiological changes seen in MSNs of D2R-OE mice.

These MSN changes parallel the behavioral changes that follow D2R manipulation in these mice, with motivation impaired in D2R-OE mice and restored when D2R overexpression is turned off (Simpson et al., 2011). Future experiments will have to determine the extent to which these changes are related, and whether antipsychotics delivered selectively to the striatum could remedy the motivational deficits in D2R-OE mice. The D2R-OE model highlights the malleability of the brain, and suggests that at least some of the fallout from the overactive dopamine signaling characteristic of schizophrenia can be reversed in adulthood.—Michele Solis.

Reference:
Cazorla M, Shegda M, Ramesh B, Harrison NL, Kellendonk C. Striatal D2 Receptors Regulate Dendritic Morphology of Medium Spiny Neurons via Kir2 Channels. J Neurosci. 2012 Feb 15. Abstract

 
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