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News Brief: Interneuron Origin Determines Glutamate Receptor Composition

July 31, 2013. Where a cortical interneuron is born determines what glutamate receptor subunits it expresses, reports a new study published online July 14, 2013, in Nature Neuroscience and led by Kenneth Pelkey, of the National Institute of Child Health and Human Development in Bethesda, Maryland.

A wide variety of interneurons, the inhibitory cells that help to shape and synchronize excitatory principal cell firing, are found throughout the cortex and hippocampus and fall into distinct categories based on their morphological, electrophysiological, and molecular properties (Ascoli et al., 2008). Subtypes of interneurons also differ in their location of origin. For example, parvalbumin- and somatostatin-containing populations derive from progenitor cells in the medial ganglionic eminence (MGE) of the ventral telencephalon, while those expressing calretinin, reelin, and cholecystokinin hail from cells in the caudal ganglionic eminence (CGE).

Proper interneuron integration into cortical circuits depends on appropriate glutamate receptor expression. In fact, mouse models that disrupt NMDA and AMPA receptors located on specific interneuron populations produce abnormal cortical synchrony and reproduce some of the symptoms of schizophrenia (see SRF related news story; SRF news story). To investigate the synaptic development of mouse hippocampal interneurons, first author Jose Matta and colleagues recorded from cells in two different reporter lines of fluorescently labeled MGE- and CGE-derived cells.

The researchers found developmental differences in NMDA and AMPA receptor composition between MGE- and CGE-derived cells. Specifically, by examining the current flow through the cells, they found that the synapses of MGE-derived interneurons relied on AMPA receptors that lacked GluA2 subunits, while those from CGE-originating interneurons used AMPA receptors that included GluA2 subunits. CGE-derived interneurons depended more on NMDA receptor-mediated current than did MGE-derived cells. While cells from the CGE expressed NR2B-containing NMDA receptors across the lifespan, cells from the MGE (including the parvalbumin cells thought to be most affected in schizophrenia) underwent a NR2B-to-NR2A switch between neonatal and juvenile time periods, and this flip could be prompted by repetitive synaptic activity.

The results establish developmental origin-regulated rules of synaptic integration for interneurons, said the authors, and “may relate to observations that early, but not late, postnatal disruption of excitatory synaptic input to specific interneuron cohorts can precipitate neurological disorders such as schizophrenia.”—Allison A. Curley.

Reference:
Matta JA, Pelkey KA, Craig MT, Chittajallu R, Jeffries BW, McBain CJ. Developmental origin dictates interneuron AMPA and NMDA receptor subunit composition and plasticity. Nat Neurosci . 2013 Aug ; 16(8):1032-41. Abstract

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Related News: Getting Specific: Conditional Knockouts Address Glutamate Hypothesis

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 (Kinney et al., 2006). Using the Cre-LoxP system to produce the selective ablation of NMDARs in mouse corticolimbic interneurons, Kazu Nakasawa and colleagues now elegantly support this hypothesis in the latest issue of Nature Neuroscience (Belforte et al., 2009). Furthermore, they demonstrate the neurodevelopmental origin of schizophrenia-like behaviors by showing that it is the dysfunction of NMDARs during the period of active maturation of PV-interneurons that increases the chance of behavioral disruptions in late adolescence/early adulthood. These results give strong support to the hypothesis that disruption of the normal maturation of PV-interneurons will produce permanent changes of the inhibitory circuitry in cortex, thus profoundly affecting cortical network function (Behrens and Sejnowski, 2009).

An interesting outcome of Belforte’s results is that, per se, the diminished activity of NMDARs in PV-interneurons does not lead to behavioral disruption, but when these animals undergo the stress of being reared in isolation they manifest the schizophrenia-like behavior. The effects of isolation rearing on PV-interneurons and behavior were recently related to the activation of the superoxide producing enzyme NADPH-oxidase (Nox2) in brain (Schiavone et al., 2009). Treatment of these animals with the Nox2 inhibitor apocynin prevented the loss of GABAergic phenotype of PV-interneurons as well as the behavioral derangements produced by the isolation rearing.

These results have bearing on the effects of NMDAR antagonist exposure, where it was shown that activation of this same enzyme (Nox2) is responsible for the effects of the antagonists on the GABAergic phenotype of PV-interneurons (Behrens et al., 2007; Behrens et al., 2008). Therefore, we can speculate that the pro-psychotic effects of NMDAR-antagonists occur by a double-hit mechanism: first, blocking NMDAR activity in PV-interneurons leads to the loss of their GABAergic phenotype; and, second, inducing the activation of the IL-6/Nox2 pathway further promotes this loss even in the absence of the antagonist. However, it is still not clear why diminished activity of NMDARs in PV-interneurons is only consequential during the period of active maturation of PV-interneuronal circuits, and renders the cortical circuitry vulnerable to the sustained activation of the IL-6/Nox2 pathway. One possible answer is that inactivation of NMDARs in PV-interneurons during early postnatal development disrupts the development of PV-interneuronal synaptic contacts. This could lead to cortical networks that have all neurons in place but with a subset dysfunctional. In turn, this faulty network may be more vulnerable to the effects of activation of the IL-6/Nox2 pathway, such that when this pathway is activated, i.e., by social isolation, it leads to aberrant oscillatory activity in brain and cognitive disruption as observed in schizophrenia.

References:

Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry. 1991 Oct 1;148(10):1301-8. Abstract

Olney JW, Newcomer JW, Farber NB. NMDA receptor hypofunction model of schizophrenia. J Psychiatr Res. 1999 Nov-Dec ;33(6):523-33. Abstract

Kinney JW, Davis CN, Tabarean I, Conti B, Bartfai T, Behrens MM. A specific role for NR2A-containing NMDA receptors in the maintenance of parvalbumin and GAD67 immunoreactivity in cultured interneurons. J Neurosci . 2006 Feb 1 ; 26(5):1604-15. Abstract

Belforte JE, Zsiros V, Sklar ER, Jiang Z, Yu G, Li Y, Quinlan EM, Nakazawa K. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat Neurosci. 2009 Nov 15. Abstract

Behrens MM, Sejnowski TJ. Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex? Neuropharmacology. 2009 Sep 1;57(3):193-200. Abstract

Schiavone S, Sorce S, Dubois-Dauphin M, Jaquet V, Colaianna M, Zotti M, Cuomo V, Trabace L, Krause KH. Involvement of NOX2 in the development of behavioral and pathologic alterations in isolated rats. Biol Psychiatry. 2009 Aug 15;66(4):384-92. Abstract

Behrens MM, Ali SS, Dao DN, Lucero J, Shekhtman G, Quick KL, Dugan LL. Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Science. 2007 Dec 7;318(5856):1645-7. Abstract

Behrens MM, Ali SS, Dugan LL. Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia. J Neurosci. 2008 Dec 17;28(51):13957-66. Abstract

View all comments by Margarita Behrens

Related News: Probing the Role of NMDA Receptor NR2B in Development and Schizophrenia

Comment by:  Stefan KolataKazu Nakazawa
Submitted 21 February 2012
Posted 21 February 2012

The original NMDA receptor (NMDAR) hypofunction theory of schizophrenia was predicated on the discovery that, in adulthood, NMDAR antagonists mimicked disease symptomatology and exacerbated symptoms in schizophrenic patients (Javitt and Zukin, 1991). Recent advances have since shown that, in addition to this effect in adulthood, there may be a postnatal developmental sensitive period necessary for NMDAR hypofunction to later manifest as schizophrenia phenotypes. For instance, in mice, schizophrenia-like phenotypes were observed when NR1 (GluN1) was ablated selectively in corticolimbic interneurons after postnatal day 7, but not when the knockout occurred after adolescence (Belforte et al., 2010). Similarly, transient antagonism of NMDA during development later resulted in schizophrenia-like phenotypes in adult rats (Stefani and Moghaddam, 2005; Baier et al., 2009). In the present work by Wang et al. (2011), using an elegant molecular genetic technique, Benjamin Hall and his colleagues were able to show that it is perhaps the NR2B (GluN2B) subunit during this developmental period that is most critical for the later development of the symptomatology. NR2B is highly expressed during this postnatal sensitive period, and is only later replaced by NR2A (GluN2A) in most NMDA receptors. The present paper showed that an early replacement of NR2B with NR2A recapitulated some of the NMDA hypomorph phenotypes. While these results are very intriguing and dovetail nicely with the emerging thinking about the neurodevelopmental role of NMDARs, the possible involvement of NR2A itself in schizophrenia should not be lost. Impairment of NR2A results in several schizophrenia-like phenotypes, including a reduction in parvalbumin immunoreactivity, impaired fast-spiking interneuron maturation, altered dopamine metabolism, and a hyperlocomotion response in the open field that is rescued by antipsychotic treatment (Zhang and Sun, 2011; Miyamoto et al., 2001). Further studies of synapses, neurons, and neuronal networks regulated by NR2A and NR2B may lead to a better understanding of the mechanisms underlying the NMDAR hypofunction theory of schizophrenia.

References:

Baier PC, Blume A, Koch J, Marx A, Fritzer G, Aldenhoff JB, Schiffelholz T. Early postnatal depletion of NMDA receptor development affects behaviour and NMDA receptor expression until later adulthood in rats--a possible model for schizophrenia. Behav Brain Res. 2009 Dec 14;205(1):96-101. Abstract

Belforte JE, Zsiros V, Sklar ER, Jiang Z, Yu G, Li Y, Quinlan EM, Nakazawa K. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat Neurosci. 2010 Jan;13(1):76-83. Abstract

Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry. 1991 Oct;148(10):1301-8. Abstract

Miyamoto Y, Yamada K, Noda Y, Mori H, Mishina M, Nabeshima T. Hyperfunction of dopaminergic and serotonergic neuronal systems in mice lacking the NMDA receptor epsilon1 subunit. J Neurosci. 2001 Jan 15;21(2):750-7. Abstract

Stefani MR, Moghaddam B. Transient N-methyl-D-aspartate receptor blockade in early development causes lasting cognitive deficits relevant to schizophrenia. Biol Psychiatry. 2005 Feb 15;57(4):433-6. Abstract

Zhang Z, Sun QQ. Development of NMDA NR2 subunits and their roles in critical period maturation of neocortical GABAergic interneurons. Dev Neurobiol. 2011 Mar;71(3):221-45. Abstract

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