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Getting Specific: Conditional Knockouts Address Glutamate Hypothesis

17 November 2009. Removing a subset of NMDA receptors during development in mice can disrupt neural circuits and behavior in ways that mirror some symptoms of schizophrenia, according to a study published online November 15 in Nature Neuroscience. Led by Kazu Nakazawa, the team of researchers based at the NIMH selectively eliminated the NMDA type of glutamate receptor from interneurons in the cortex and hippocampus of mice early in development and in adulthood.

When they induced NR1 loss early in development, a host of brain and behavior anomalies reminiscent of schizophrenia developed in late adolescence for the mice. These anomalies did not emerge, however, when NMDA receptor loss occurred in adulthood. This difference bolsters the idea that early problems in brain development may remain latent until later in life.

The approach tests some specifics of the glutamate hypothesis proposed for schizophrenia, which originally stemmed from the observation that drugs that block NMDA receptors throughout the brain can induce schizophrenia-like features in animals and humans (see SRF related hypothesis and SRF hypothesis). This led to the notion that underactive NMDA receptors (or "NMDA hypofunction") could be a primary problem in schizophrenia, and could then drive imbalances in other neurotransmitter systems throughout the brain (see SRF related news story). For example, underactive NMDA receptors lead to GABAergic malfunction in interneurons in mice, as shown by the loss of parvalbumin, a calcium binding protein, and GAD67, an enzyme that helps synthesize GABA (Behrens et al., 2007). Intriguingly, these two proteins are also reduced in some interneurons in postmortem brains of people who died with schizophrenia (Hashimoto et al., 2003).

Let’s make it conditional
When exploring the glutamate hypothesis, manipulations of NMDA function have been relatively coarse, affecting all NMDA receptors throughout the brain. Nakazawa and colleagues wanted to get more specific by testing the effects of eliminating NMDA receptors in a targeted cell type, in selected brain regions, and at precise times of development. They did this by engineering "conditional knockout" mice that did not have the essential NR1 subunit of the NMDA receptor in about half the interneurons located in the cortex and hippocampus.

First author Juan Belforte and colleagues verified that NR1 loss was restricted to interneurons. Under the microscope, brain tissue from mutant mice had the expected number of interneurons, but about half of these lacked NR1 mRNA. In controls, pretty much all interneurons—as inferred by staining for GAD67—were positive for NR1 mRNA. Yet, NR1 was unperturbed in other cell types, as judged by the normal number of GAD67-negative cells that also contained NR1 mRNA. Interneurons that lacked NR1 mRNA were found in medial prefrontal cortex, somatosensory cortex, hippocampus, but not striatum or basolateral amygdala. As expected, the loss of NR1 mRNA scrapped the NMDA receptor: when the team recorded from these interneurons in brain slices, they found a distinct lack of NMDA currents.

Those cells that lost NR1 early in development went on to mimic in late adolescence the reduced GAD67 and parvalbumin levels also found in schizophrenia. This suggests that these interneurons, while functional, are not up to snuff. Indeed, evidence for this came from in vivo recordings of pyramidal cells, which are inhibited by signals from interneurons: they fired at higher rates than usual, with less synchrony. These data suggest that the interneurons had trouble keeping a lid on pyramidal cell activity, and this kind of cortical "disinhibition" has been previously proposed as a downstream effect of NMDA hypofunction (Lisman et al., 2008).

In many ways these mice seemed normal behaviorally, but when stressed, they struggled. After a week or more of "social isolation stress" in which the mice were housed by themselves, they developed a number of unusual behaviors. They scored higher on measures of anxiety, for example, avoiding the center of an open-field environment more than controls did. In the social domain, they were not much good at building nests and they had social memory deficits, sniffing a mouse they had already interacted with as though for the first time. Short-term memory was impaired, with the mice failing to adapt an alternating pattern of entries between the two arms of a Y-shaped maze. And, as in some patients with schizophrenia, prepulse inhibition was substantially decreased.

The mice that lost the NR1 subunit as adults were a different story, however. When examined five weeks after losing NR1 (to match the delay between NR1 loss and testing in the previous group of mice), these mice showed no differences when compared to controls: their interneurons had the expected levels of GAD67 and parvalbumin, their excitatory cortical neurons fired normally, and they sailed through their battery of behavioral tests.

This indicates that NMDA receptors play a key role early in postnatal development for these interneurons, beyond merely providing a conduit for excitatory signals. The authors suggest that NMDA receptors influence interneuron maturation; without them, the interneurons and the neural circuits they participate in are disturbed, which may ultimately increase susceptibility to psychiatric illness. While this study in mice doesn't clarify whether schizophrenia is at its core a glutamate disorder, it does draw specific connections between NMDA hypofunction, neural circuits, and behavior that may inform further research on the glutamate hypothesis of schizophrenia.—Michele Solis.

Reference:
Belforte J, Zsiros V, Sklar E, Jiang Z, Yu G, Li Y, Quinlan E, Nakazawa K. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nature Neuroscience 2009. Abstract

 
Comments on News and Primary Papers
Comment by:  Margarita Behrens
Submitted 17 November 2009 Posted 17 November 2009

Since the discovery that phencyclidine and its analog ketamine exert their pro-psychotic effects through antagonism of NMDA receptors (Javitt and Zukin, 1991), the mechanisms by which these drugs exert these effects have been the subject of intensive research. These studies led to the hypo-NMDA theory of schizophrenia by Olney and collaborators that proposed that “blockade of NMDA receptors triggers a complex network disturbance featuring inactivation of inhibitory neurons and consequent disinhibition of excitatory pathways…” (Olney et al., 1999). Based on the effects of prolonged exposure of primary cultured neurons to selective and non-selective NMDAR antagonists, it was proposed that NMDARs expressed by the subpopulation of parvalbumin-positive (PV) fast spiking interneurons were the target of the antagonists, and that these glutamate receptors played a fundamental role in the maintenance of the GABAergic phenotype of the interneurons (  Read more


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