8 Jan 2015
January 9, 2015. The glutamate hypothesis of schizophrenia, which suggests that impaired signaling through NMDA receptors is a core aspect of illness pathophysiology, continues to be one of the field's most researched (see SRF hypotheses by Daniel Javitt and Bita Moghaddam). In the spirit of last year's interneuron poster tour of SfN 2013 (see SRF related news report), a similar guide to schizophrenia-related glutamate posters was compiled from this year's meeting in Washington, DC. Just as in 2013, the huge number of posters this year precludes comprehensive coverage; what follows is only a sample of the results presented. (If we didn't get to your poster, feel free to share your main findings in a comment below.)
Of mice, monkeys…
A Saturday afternoon poster presented by Xiaodong Zhang from Duke-NUS Graduate Medical School in Singapore discussed evidence suggesting that the endogenous neurosteroid pregnanolone sulfate (PregS), a positive allosteric modulator of the NMDA receptor, could be beneficial in schizophrenia. A previous study showed that acute PregS treatment improved hyperactivity and prepulse inhibition deficits, while chronic administration improved cognitive problems, in the dopamine transporter knockout mouse model that recapitulates some aspects of the illness. In an effort to identify the pathway underlying this effect, in the current study the researchers examined the effect of the NMDA antagonist MK-801 on these behaviors in wild-type mice. Consistent with a role for NMDA receptor signaling in the actions of PregS, acute administration of the neurosteroid reversed the MK-801-induced hyperactivity and prepulse inhibition deficits. Delving deeper into the pathway underlying the effect of PregS, the researchers found that the neurosteroid also reduced deficits in the phosphorylation of AKT and GSK-3_ in the striatum, and elevated hippocampal NR1 mRNA levels, in DAT knockouts.
Also on Saturday afternoon, Matthew Puhl from McLean Hospital in Belmont, Massachusetts, presented MRI and magnetic resonance spectroscopy (MRS) findings validating a serine racemase (SR) knockout mouse model of schizophrenia. SR is the enzyme that makes NMDA receptor co-agonist D-serine, and SR knockouts display NMDA receptor hypofunction. Coupled with findings that several SR-related genes elevate risk for the illness, decreased availability of SR is hypothesized to be a mechanism underlying the NMDA receptor hypofunction posited to exist in schizophrenia. In the current study, Puhl and colleagues reported that the SR knockouts display several abnormalities that are also found in schizophrenia: cortical atrophy, ventricular enlargement, and elevated levels of both glutamate and GABA. The researchers conclude that their mouse model suggests SR may play a role in NMDA hypofunction in schizophrenia and will be valuable for investigating glutamatergic abnormalities in the illness.
On Tuesday afternoon, Valerie Bertaina-Anglade of Biotrial Pharmacology, Rennes, France, presented rodent data on the efficacy of bitopertin, an inhibitor of the transporter for NMDA receptor co-agonist glycine (GlyT1), and tolcapone, a catechol-O-methyltransferase (COMT) inhibitor, in treating correlates of negative and cognitive symptoms in the phencyclidine (PCP) model of schizophrenia. At a poster presented last year at SfN, the researchers showed that subchronic treatment with PCP induced social impairments (measured with the social interaction test) and memory deficits (measured with a novel object recognition task). In the new study, the researchers explored the duration of the PCP-induced impairments and examined the efficacy of bitopertin and tolcapone in reversing them. Social withdrawal endured for nine weeks following the end of PCP treatment, while the memory impairment lasted for four weeks. Only the two higher doses of acute bitopertin were able to reverse the social impairment (and did not affect the memory problem), while all three doses of tolcapone were effective in counteracting the memory deficit (but not the social difficulty). The researchers conclude that this model could be used to identify novel antipsychotics.
Also in the Tuesday afternoon session, Eric Maltbie of the Yerkes National Primate Research Center in Atlanta, Georgia, reported on the development of a non-human primate model to evaluate antipsychotic efficacy. Maltbie and colleagues previously created a method to conduct fMRI evaluations in awake rhesus monkeys. In the current study, the researchers administered a sub-anesthetic dose of ketamine prior to the scan and found that ketamine produced a pattern of activation in the monkeys that was “strikingly similar" to that observed in humans, said Maltbie. In both humans and monkeys, the greatest activation in response to ketamine occurred in the thalamus, cingulate cortex, and dorsal striatum. Also similar to the illness, the administration of risperidone in monkeys reduced the activity in these brain areas. The findings indicate that this ketamine paradigm in rhesus monkeys is a reliable and translatable model in which to test antipsychotic efficacy.
On Sunday afternoon, Dibyadeep Datta of the University of Pittsburgh, Pennsylvania, discussed the molecular mechanisms underlying the reduction in the density of dendritic spines on glutamatergic pyramidal cells in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia. Based on prior evidence from the group demonstrating that the Rho family of GTPases, key regulators of the actin cytoskeleton, are dysregulated in DLPFC total gray matter in schizophrenia, Datta and colleagues undertook a more thorough analysis of the Rho GTPase Cdc42 and related proteins in single pyramidal neurons. While Cdc42 and upstream regulators of the pathway were decreased in the schizophrenia neurons, the opposite was true for the mRNA levels of the downstream regulators/effectors. The researchers conclude that the reduction in upstream regulators may contribute to a diminished stability of spines, while the increase in downstream pathway members could reflect a compensation to improve synaptic plasticity by enhancing the stability of the remaining spines.
On Tuesday afternoon, Teppei Tanaka of Johns Hopkins University in Baltimore, Maryland, presented a study measuring the levels of glutathione (GSH), a marker of oxidative stress, in schizophrenia. A reduction in the levels of total GSH was found in the both the plasma and lymphocytes of patients, though levels assessed using MRS were unchanged in the anterior cingulate cortex of the same subjects. Total plasma GSH levels were significantly correlated with anterior cingulate glutamate levels as well as with cognitive deficits—both composite scores as well as performance specifically in verbal memory and processing speed. These findings not only suggest a link between glutamatergic abnormalities and peripheral oxidative stress in schizophrenia, but they also suggest that peripheral GSH levels are a potential biomarker for the illness.—Allison Marin.