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Research Roundup: PV Interneurons and Neural Circuit (Dys)Function

January 21, 2014. It takes a village of diverse neurons to make a brain, and among the villagers, parvalbumin (PV)-containing interneurons hold a special position. Comprising 25 percent of interneurons in primate cortex, these cells are critical synchronizers of neural activity. Rodent studies find them to be involved in timing neural activity, plasticity, and sustaining newborn neurons, and in schizophrenia, postmortem brain studies find signs of weakened inhibition by PV interneurons. Here, SRF reviews recent developments in PV interneuron biology, including two studies specific to schizophrenia, which bolster the proposition that PV interneurons are structurally sound but functionally compromised in the disorder.

Dysfunction in a circuit nexus
“We have to think about these neurons at the level of the circuit in which they are embedded,” said David Lewis of the University of Pittsburgh, Pennsylvania, who was involved in both studies. Lewis has been a driving force in identifying molecular abnormalities in PV interneurons and their pyramidal neuron counterparts in postmortem studies of people with schizophrenia (see SRF interview).

In the cortex, PV interneurons inhibit multiple pyramidal cells, which then feed back onto PV interneurons with excitatory inputs. This circuit creates a cycle of excitation and inhibition that gives rise to γ oscillations—coordinated fluctuations in neural activity across the brain at about 40 Hz (see SRF related news report)—which appear to be important for cognition. PV interneurons provide a synchronizing signal to many pyramidal cells, and the duration of their inhibitory inputs sets the timing of the rhythmic activity.

Lewis and colleagues have uncovered molecular differences in postmortem brain samples from people with schizophrenia that suggest that, in dorsolateral prefrontal cortex (DLPFC), PV interneurons do not suppress their pyramidal cell targets as they should: For example, PV interneurons are deficient in GAD67, the enzyme that makes the inhibitory neurotransmitter γ-aminobutyric acid (GABA), and their pyramidal cell targets show a decrease in GABA receptors (Lewis et al., 2012). Furthermore, Beretta and colleagues have found fewer numbers of perineuronal nets surrounding PV interneurons, which may protect the cells from the ravages of oxidative stress that come with their rapid firing (see SRF related news report). These and other alterations may undermine PV interneuron function and contribute to the disrupted γ oscillations—and cognitive difficulties—observed in schizophrenia (Uhlhaas et al., 2012; see SRF related news report).

Not only do PV interneurons run low on GAD67, but also on PV itself. This makes identifying them tricky, because PV is the marker of choice for these interneurons. The new studies address this with a careful accounting of PV levels in specific synapses and with an altogether different marker of a potassium channel subunit that selectively labels PV interneurons.

More molecules
The first study, from the Lewis lab with first authors Jill Glausier and Ken Fish, localizes the PV deficit to the axon terminals where the GABA-releasing machinery resides. Published online November 12 in Molecular Psychiatry, the study applied a technique that precisely pinpoints the location of three different labels: one for PV, one for the GABA-making enzyme GAD65, which is only found in axon terminals, and one for the GABA receptor α1 subunit, which characterizes synapses of basket cells, a subtype of PV interneurons that innervates the cell bodies and dendrites of pyramidal cells. Overlap among all three labels, then, specifically marked basket cell inputs.

In schizophrenia DLPFC samples, the basket cell inputs were just as numerous, in terms of density, as those in controls, but with decreased levels of PV. In combination with the decreased GAD67 found in these terminals (Curley et al., 2011), the findings suggest that the function rather than the structure of these inputs is altered in schizophrenia, and that finding ways to modulate these connections may restore the circuit.

The second study, published online October 30 in the American Journal of Psychiatry reports that PV interneurons lack the potassium channel subunits encoded by KCNS3 in schizophrenia. Earlier work had fingered KCNS3 as a specific marker for PV interneurons (Georgiev et al., 2012). The new study evaluated KCNS3 transcript levels in schizophrenia and found them lacking by two distinct methods: in-situ hybridization in one group of postmortem samples, and laser microdissection of PV interneurons followed by microarray measurement of mRNA in a different group of samples. Led by Takanori Hashimoto of Kanazawa University in Japan, in collaboration with Lewis, the study reports that KCNS3 levels were lower by 23 percent with in-situ hybridization and 40 percent lower by microarray.

First author Danko Georgiev and colleagues propose that this deficit would disrupt synchronous firing in cortical circuits. KCNS3 subunits normally offset excitation and so limit the duration of excitatory inputs. This would allow for only simultaneous inputs to evoke a spike. With fewer KCNS3 subunits around, however, the excitatory inputs received by PV interneurons would be prolonged, increasing the chances for overlap, and spiking, with unsynchronized inputs.

“So this reduced KCNS3 could, in and of itself, provide a molecular basis for impaired γ oscillations,” Lewis said. “What we're uncertain of right now is—how does it fit together with less GAD67?” He suggests that people with schizophrenia could have just one of these deficits, or, alternatively, both deficits may be required to bring about a disease-related pathology.

PV for plasticity
These molecular alterations seem to stem from disruptions to brain development rather than being consequences of schizophrenia onset, according to a recent analysis by Lewis and colleagues (Hoftman et al., 2013). For example, PV levels found in the postmortem studies do not vary according to duration of illness, but rather fall short of a normal increase occurring during adolescence.

But PV levels may be quite malleable in adulthood, according to a study published December 12 in Nature. Led by Pico Caroni of the Friedrich Miescher Institute in Basel, Switzerland, the study reports that experience alters PV levels in hippocampal PV interneurons in mice, which then dictates the plasticity state of the circuit. First author Flavio Donato and colleagues report that mice spending time in an enriched environment, with lots of things to play with and explore, had more PV interneurons, specifically basket cells, classified as “low-PV expressers,” than mice raised in a standard cage and mice that had been fear conditioned with electric shocks in their cage. Conversely, the fear-conditioned mice had a greater percentage of PV interneurons rated as “high-PV-expressers.” Changes in the types of synapses made onto PV interneurons also varied according to PV levels: Low-PV interneurons received mostly inhibitory inputs, whereas in high-PV interneurons, excitatory inputs predominated. Directly manipulating the activity of PV interneurons with optogenetics also brought about these changes. This suggests that experience can shift the hippocampal circuits between low-PV or high-PV configurations.

Further experiments suggested that low-PV configurations promoted the process of learning, in which new associations are made, but remain labile to take new information into account, whereas high-PV configurations allowed the establishment of strong memories. Interestingly, stimulating vasoactive intestinal peptide (VIP)-containing inputs to the hippocampus induced a low-PV configuration; the gene encoding a receptor for VIP has been linked to schizophrenia (see SRF related news report). The researchers suggest that finding ways to shift between low- and high-PV configurations could promote cognition.

Whether this insight might apply to schizophrenia depends on how much the hippocampal circuit in mice resembles that in humans. “Sometimes the literature seems to act as if a PV neuron is a PV neuron is a PV neuron, but we have to pay attention to species differences,” Lewis said. In the mouse cortex, for example, 50 percent of interneurons express PV, compared to 25 percent in primates, including humans, and this could influence species-specific differences in the resulting circuits.

Still, two other mouse studies point to additional roles for PV interneurons worth noting. One, published November 20 in Nature, is in keeping with their role as synchronizers. Led by Cyril Herry at the University of Bordeaux, France, the researchers found that optogenetically inhibiting PV interneurons in mouse cortex resets activity in their target pyramidal cells, inducing them to fire simultaneously. First author Julien Courtin and colleagues found that this promoted theta oscillations, which vary more slowly than γ oscillations, and drove the expression of a fear memory.

Another paper, published November 10 in Nature Neuroscience, reports that PV interneurons support newly born neurons in the adult hippocampus of mice. Hongjun Song and Guo-li Ming of Johns Hopkins University in Baltimore, Maryland, joined forces with Nicolas Toni of the University of Lausanne, Switzerland, to study PV interneuron involvement in adult neurogenesis. They found that suppressing PV interneuron activity led to a die-off of newborn neurons, whereas increased activity promoted their survival. In contrast, the group’s earlier study found that PV interneurons suppress stem cells from making new neurons in the first place (Song et al., 2012). Activity in PV interneurons, then, could convey a circuit’s need for new neurons.

Therapeutic avenue
Finding ways to selectively modulate PV interneurons seems like a possible therapeutic strategy for schizophrenia. One recent idea comes from a study of the neuregulin-ErbB4 signaling pathway, which is found primarily in PV interneurons and has been linked to schizophrenia through genetics and animal studies (e.g., see SRF related news report). Led by Andres Buonanno of the National Institute of Child Health and Human Development in Bethesda, Maryland, and published online November 11 in Proceedings of the National Academy of Sciences, the study reports that neuregulin binding to the ErbB4 receptor on PV interneurons in the rat hippocampus can activate the internalization of GABA receptors in the hippocampus. First authors Robert Mitchell and Megan Janssen found that this action, however, did not involve the typical tyrosine kinase activity of ErbB4. This suggests a new mode of signaling that may fine-tune inhibitory inputs onto PV interneurons and affect the inhibitory network in the hippocampus. Though GABA receptor deficits have been noted mostly for pyramidal cells in the neocortex in schizophrenia, the results suggest that the GABA receptors in PV interneurons could matter for hippocampus function, which also appears to be compromised in schizophrenia (see SRF Live Discussion).—Michele Solis.

Glausier JR, Fish KN, Lewis DA. Altered parvalbumin basket cell inputs in the dorsolateral prefrontal cortex of schizophrenia subjects. Mol Psychiatry. 2014 Jan;19(1):30-6. Abstract

Georgiev D, Arion D, Enwright JF, Kikuchi M, Minabe Y, Corradi JP, Lewis DA, Hashimoto T. Lower Gene Expression for KCNS3 Potassium Channel Subunit in Parvalbumin-Containing Neurons in the Prefrontal Cortex in Schizophrenia. Am J Psychiatry. 2014 Jan 1;171(1):62-71. Abstract

Donato F, Rompani SB, Caroni P. Parvalbumin-expressing basket-cell network plasticity induced by experience regulates adult learning. Nature. 2013 Dec 12;504(7479):272-6. Abstract

Courtin J, Chaudun F, Rozeske RR, Karalis N, Gonzalez-Campo C, Wurtz H, Abdi A, Baufreton J, Bienvenu TC, Herry C. Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression. Nature. 2014 Jan 2;505(7481):92-6. Abstract

Song J, Sun J, Moss J, Wen Z, Sun GJ, Hsu D, Zhong C, Davoudi H, Christian KM, Toni N, Ming GL, Song H. Parvalbumin interneurons mediate neuronal circuitry-neurogenesis coupling in the adult hippocampus. Nat Neurosci. 2013 Dec;16(12):1728-30. Abstract

Mitchell RM, Janssen MJ, Karavanova I, Vullhorst D, Furth K, Makusky A, Markey SP, Buonanno A. ErbB4 reduces synaptic GABAA currents independent of its receptor tyrosine kinase activity. Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19603-8. Abstract

Comments on News and Primary Papers
Comment by:  Takao Hensch
Submitted 15 February 2014
Posted 15 February 2014

Our Conte Center is focused on the transcriptome, connectome, and plasticity of PV cells as the neurodevelopmental basis for mental illness. Their maturational state dictates the degree of plasticity in developmental critical periods, and now we know, from Donato et al., in adult learning. Once plasticity is opened by PV cells' function, it closes when they mature ("high PV" state), including the tightening of the perineuronal nets (PNNs) around them.

In schizophrenia, PV cells may remain in the "low PV" weak PNN state for some time longer than normal, suggesting, interestingly, that developmental plasticity may be prolonged (i.e., neural circuits fail to stabilize when they normally should). PV cell maturation may potentially be controlled by Otx2 secreted from the choroid plexus, which would link enlarged ventricles to impaired PV cells in the brain in schizophrenia (see Spatazza et al., 2013).


Spatazza J, Lee HH, Di Nardo AA, Tibaldi L, Joliot A, Hensch TK, Prochiantz A. Choroid-plexus-derived Otx2 homeoprotein constrains adult cortical plasticity. Cell Rep. 2013 Jun 27;3(6):1815-23. Abstract

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Comments on Related News

Related News: Asynchrony and the Brain—Gamma Deficits Linked to Poor Cognitive Control

Comment by:  Richard Deth
Submitted 14 December 2006
Posted 15 December 2006

Schizophrenia is associated with dopaminergic dysfunction, impaired gamma synchronization and impaired methylation. It is therefore of interest that the D4 dopamine receptor is involved in gamma synchronization (Demiralp et al., 2006) and that the D4 dopamine receptor uniquely carries out methylation of membrane phospholipids (Sharma et al., 1999). A reasonable and unifying hypothesis would be that schizophrenia results from a failure of methylation to adequately support dopamine-stimulated phospholipid methylation, leading to impaired gamma synchronization. Synchronization in response to dopamine can provide a molecular mechanism for attention, as information in participating neural networks is able to bind together to create cognitive experience involving multiple brain regions.

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Related News: Asynchrony and the Brain—Gamma Deficits Linked to Poor Cognitive Control

Comment by:  Fred Sabb
Submitted 12 January 2007
Posted 12 January 2007
  I recommend the Primary Papers

Cho and colleagues find patients with schizophrenia showed a reduction in induced gamma band activity in the dorsolateral prefrontal cortex compared to healthy control subjects during a behavioral task that is known to challenge cognitive control processes. Importantly, the induced gamma band activity was correlated with better performance in healthy subjects, and negatively correlated with higher disorganization symptoms in patients with schizophrenia. These findings help explain previous post-mortem evidence of disruptions in thalamofrontocortical circuits in these patients.

These findings tie together several different previously identified phenotypes into a unifying story. The ability to link phenotypes across translational research domains is paramount to understanding complex neuropsychiatric diseases like schizophrenia. Cho and colleagues provide an excellent example for connecting evidence from symptom rating scales with behavioral, neural systems and neurophysiological data. Although not specifically addressed by the authors, these data may have important implications for understanding the neural basis of thought disorder as well. Hopefully, these findings will provide a frame-work for examining more informed and specific phenotypes relevant to schizophrenia.

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Related News: Commentary Brief: Optogenetics Links Interneurons and γ Oscillations

Comment by:  Guillermo Gonzalez-Burgos
Submitted 24 July 2009
Posted 24 July 2009

Blue light, yellow light, and the role of parvalbumin-positive neurons in the pathophysiology of schizophrenia
Parvalbumin (PV)-positive cells are a prominent subtype of GABA neuron that via perisomatic synapses may strongly inhibit pyramidal cell activity (however, see Szabadics et al., 2006). In schizophrenia, PV neurons have reduced levels of mRNA for PV and for GAD67, the 67 kilodalton form of the GABA-synthesizing enzyme glutamate decarboxylase. The functional consequences of the PV reduction in schizophrenia are poorly understood, but one possibility is that decreased PV partially compensates for a deficit in GABA release caused by the GAD67 reduction. PV is a slow Ca2+ buffer, and so decreasing PV in nerve terminals may facilitate GABA release during repetitive PV cell firing (for a review, see Gonzalez-Burgos and Lewis, 2008).

Why is PV cell-mediated inhibition significant to brain function? What deficits in cortical circuit function may be compensated for (at least partially) by a decrease of PV in schizophrenia? The answers to these questions depend on our knowledge of the functional role of PV neurons in cortical circuits. A leading hypothesis in this regard suggests that PV cells are essential for the production of synchronized oscillations in cortex, particularly in the γ frequency band (Bartos et al., 2007). γ oscillations are thought to be important for the transmission of information within and between neocortical areas (Salinas and Sejnowski, 2001). If so, then γ activity must be important for cognition, which is critically dependent on the flow of information across the neocortex (Singer, 1999; Fuster, 2004). Therefore, cognitive deficits (a key feature of schizophrenia) may result from the impairment of γ oscillations reported in the illness, which in turn could be a consequence of deficits in PV cell-mediated inhibition.

How is PV cell-mediated inhibition linked to the production of γ oscillations? PV neurons alone are not sufficient to produce network oscillations because, although PV cell membranes resonate at γ frequency (Pike et al., 2000), PV neurons actually lack intrinsic pacemaker activity. Therefore, whereas PV cells may be necessary to produce γ oscillations, synaptic interactions with other cell types in the cortical circuit must be necessary as well.

Studying the link between PV neuron activity and γ oscillations is complicated by the lack of tools available to selectively manipulate PV cell activity. Interestingly, two recent studies (Sohal et al., 2009; Cardin et al., 2009) employed novel “optogenetic” methods in mice, to further advance our understanding of how PV neurons are involved in γ oscillations.

Using viral vectors to drive cell type-specific expression of recombinant genes, Sohal and colleagues, as well as Cardin et al., produced expression of microbial opsins (which are light-sensitive ion channel proteins) selectively in specific populations of cortical neurons. Briefly described, modulation of neuronal activity using such optogenetic techniques works as follows: in cells expressing channelrhodopsin-2 (ChR2), illumination with blue light produces a depolarizing current that has excitatory effects (increases cell firing). On the other hand, cells expressing halorhodopsin (eNpHR) respond to yellow light with a hyperpolarizing current that has inhibitory effects (decreases cell firing). In this way, light of different wavelengths can be used to either inhibit or excite PV cells or pyramidal (PYR) neurons in the mouse cortex (in vivo or in vitro) in different experimental designs.

Sohal and colleagues first demonstrated that inhibiting the activity of eNpHR-expressing PV neurons with yellow light suppresses γ oscillations generated in vivo by rhythmic flashes of blue light applied to stimulate nearby ChR2-expressing PYR neurons. Furthermore, they show that non-rhythmic excitation of PYR cells produces non-rhythmic PYR cell firing. However, if the non-rhythmic PYR spikes are used to trigger feedback inhibition by PV neurons (driven by blue light flashes that stimulate ChR2-expressing PV cells), the addition of feedback inhibition induces a γ rhythm in PYR cell output. These results show that by means of recurrent interactions with pyramidal cells (consistent with the so-called PING models of γ rhythms; Whittington et al., 2000), PV cell activity is crucial for γ oscillations.

Finally, the experiments performed by Sohal et al. suggest that γ activity may selectively enhance the flow of information in cortical circuits. For example, their experiments demonstrate that the gain of the neuronal input-output relation (that is, the slope of the curve describing the transformation of inputs into outputs) is specifically enhanced when excitatory inputs onto a PYR cell are modulated rhythmically at γ frequency. Moreover, the amount of information flowing across synapses during interactions between PYR and PV neurons was estimated using concepts derived from information theory. The estimates from Sohal et al. showed that when network activity was driven by trains of blue flashes delivered at γ frequency, information transmission was markedly enhanced.

Using somewhat different genetic engineering approaches, Cardin and colleagues produced cell type-specific expression of ChR2 in PV cells or PYR neurons. Expression of ChR2 in PV cells of the mouse barrel (somatosensory) cortex allowed the activation of PV neurons with rhythmic flashes of light. Such manipulation produced rhythmic population activity (as detected recording local field potentials) more strongly when PV cells were driven at γ frequency compared with other frequencies. They report, in addition, some data showing that manipulation of PV cell activity has an impact on γ oscillations intrinsically generated by the cortical circuits, as opposed to γ rhythms induced by rhythmic stimuli applied by the investigators. For example, brief flashes of blue light applied to stimulate firing of ChR2-expressing PV neurons during spontaneous γ activity were able to reset the phase of the γ rhythm. Cardin et al. also demonstrate that activation of ChR2-expressing PV neurons can suppress the somatosensory response (to whisker stimulation) of nearby PYR cells. Then they go on to test an important functional role predicted for γ oscillations: that cells in a local network engaged in γ oscillations may respond differently to incoming inputs, depending on the timing of the incoming inputs relative to the phase of the γ cycle (Fries et al., 2007). In an elegant experiment, the investigators paired brief whisker stimulation with rhythmic flashes of blue light which, by stimulating ChR2-expressing PV cells, generate a γ rhythm locally. The crucial finding from this experiment is that the excitatory power of whisker stimulation was strongly dependent on the γ cycle phase at which whisker stimulation was delivered.

The data from these two recent studies briefly summarized above further consolidate the notion that PV-positive GABA neurons are key players in the mechanisms of γ synchrony in cortex. The data from these studies confirm that rhythmic PV neuron firing at γ frequency is sufficient to generate a γ rhythm in the population of postsynaptic neurons. This is not the same, however, as saying that PV neurons alone are sufficient to generate γ. Indeed, the data from these two studies point to the idea that PV neurons work in close interaction, via feedback loops, with nearby pyramidal cells. This makes sense, given that PV neurons are not intrinsic pacemakers. γ rhythms, therefore, seem to originate in complex network interactions that require the coordinated activity of pyramidal neurons, PV cells, and possibly other GABA neuron subtypes as well.

These two studies also highlight the similar importance of PV cell-dependent γ oscillations across different regions of cortex primarily involved in very different functions: Sohal and colleagues studied the role of PV neurons in frontal cortical areas, whereas Cardin et al. manipulated PV cell activity in the primary somatosensory cortex. The similarity of the findings regarding PV neuron function suggests that these neurons probably play a very similar role, at the microcircuit level, in these two very different cortical areas. Interestingly, deficits in GABA transmission, as assessed in postmortem brain studies, appear to be found in multiple areas of cortex simultaneously (Hashimoto et al., 2008). If this is indeed the case, then an impairment of γ oscillations may be present in most cortical areas. Thus, deficits in PV cell-dependent γ rhythms may explain the impairment of not only complex cognitive functions (for example, working memory), but also of more basic sensory processing which, as reviewed elsewhere (Javitt, 2009), is also impaired in schizophrenia. Finding a global deficit of GABA transmission and γ oscillations, as opposed to a deficit restricted to a single cortical area, increases the probability of success in developing pharmacological treatments.

A better understanding of the functional role of PV neurons in normal cortical circuits is crucial to developing better models that could explain how alterations of PV cells (and of other GABA neurons subtypes) originate in schizophrenia. As highlighted elsewhere (Lewis and Gonzalez-Burgos, 2008), any given alteration observed in schizophrenia may represent 1) cause, an upstream factor related to the disease pathogenesis; 2) consequence, a deleterious effect of a cause; 3) compensation, a response to either cause or consequence that helps restore homeostasis; or 4) confound, a product of factors frequently associated with, but not a part of, the disease process, or an artifact of the approach used to obtain the measure of interest. A major challenge for schizophrenia research is therefore determining to which of the four “C” categories each alteration belongs (Lewis and Gonzalez-Burgos, 2008). Certainly, information from basic neuroscience research studies such as those of Sohal et al. and Cardin et al. and many other past and future studies is extremely helpful in achieving this goal.


Szabadics J, Varga C, Molnar G, Olah S, Barzo P, Tamas G: Excitatory effect of GABAergic axo-axonic cells in cortical microcircuits. Science 311:233-235, 2006. Abstract

Gonzalez-Burgos G, Lewis DA: GABA Neurons and the Mechanisms of Network Oscillations: Implications for Understanding Cortical Dysfunction in Schizophrenia. Schizophr Bull 34:944-961, 2008. Abstract

Bartos M, Vida I, Jonas P: Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks. Nat Rev Neurosci 8:45-56, 2007.Abstract

Salinas E, Sejnowski TJ: Correlated neuronal activity and the flow of neural information. Nat Rev Neurosci 2:539-550, 2001. Abstract

Singer W: Neuronal synchrony: a versatile code for the definition of relations? Neuron 24:111-25, 1999. Abstract

Fuster JM: Upper processing stages of the perception-action cycle. Trends Cogn Sci 8:143-145, 2004. Abstract

Pike FG, Goddard RS, Suckling JM, Ganter P, Kasthuri N, Paulsen O: Distinct frequency preferences of different types of rat hippocampal neurones in response to oscillatory input currents. J Physiol 529 Pt 1:205-213, 2000. Abstract

Sohal VS, Zhang F, Yizhar O, Deisseroth K: Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 2009 Jun 4;459(7247):698-702. Abstract

Cardin JA, Carlen M, Meletis K, Knoblich U, Zhang F, Deisseroth K, Tsai LH, Moore CI: Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature 2009 Jun 4;459(7247):663-7. Abstract

Whittington MA, Traub RD, Kopell N, Ermentrout B, Buhl EH: Inhibition-based rhythms: experimental and mathematical observations on network dynamics. Int J Psychophysiol 38:315-336, 2000. Abstract

Fries P, Nikolic D, Singer W: The gamma cycle. Trends Neurosci 30:309-316, 2007. Abstract

Hashimoto T, Bazmi HH, Mirnics K, Wu Q, Sampson AR, Lewis DA: Conserved Regional Patterns of GABA-Related Transcript Expression in the Neocortex of Subjects With Schizophrenia. American Journal of Psychiatry 162:479-489, 2008. Abstract

Javitt DC: When doors of perception close: bottom-up models of disrupted cognition in schizophrenia. Annu Rev Clin Psychol 5:249-275, 2009. Abstract

Lewis DA, Gonzalez-Burgos G: Neuroplasticity of neocortical circuits in schizophrenia. Neuropsychopharmacology 33:141-165, 2008. Abstract

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Related News: ErbB4 Deletion Models Aspects of Schizophrenia

Comment by:  Beatriz RicoOscar Marin
Submitted 30 October 2013
Posted 5 November 2013

We would like to provide an answer to the question raised by Andrés Buonanno: “If the knockouts have more γ power, why do they perform less well on the Y maze?” As explained in the manuscript, the abnormal increase in γ power observed in conditional ErbB4 mutants would not necessarily lead to better performance, because interneurons are not pacing pyramidal cells at the proper/normal rhythm. In addition, local hypersynchrony seems to affect long-range functional connectivity: We showed a prominent decoupling between the hippocampus and prefrontal cortex. The increase in excitability and synchrony, and the decoupling between the hippocampus and prefrontal cortex, are likely the cause of the behavioral deficits in cognitive function.

In line with this, we respectfully disagree with Buonanno's next comment that “these data are also at odds with what has been observed in schizophrenia.” Indeed, as we mentioned in the manuscript, recent studies indicate that medication-naive, first-episode, and chronic patients with schizophrenia show elevated γ-band power in resting state. Baseline increases in γ oscillations are consistent with increases in the excitatory/inhibitory ratio of cortical neurons. Thus, cortical rhythm abnormalities in schizophrenia seem to include both abnormal increases in baseline power—as we observed in conditional ErbB4 mutants—as well as deficits in task-related oscillations (Uhlhaas and Singer, 2012).


Uhlhaas PJ, and Singer W. (2012). Neuronal dynamics and neuropsychiatric disorders: toward a translational paradigm for dysfunctional large-scale net- works. Neuron 75, 963–980. Abstract

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Related News: New Antipsychotic Drug? Bypassing the NMDA Receptor With mGluR5

Comment by:  Foster Olive
Submitted 5 June 2015
Posted 7 June 2015

These exciting findings represent a paradigm shift in current theories and drug development efforts for neuropsychiatric disorders. The ability of this novel mGluR5 PAM to produce behavioral effects independent of secondary NMDA receptor activation has implications that extend into numerous areas of neuroscience. Recent work by our laboratory and others indicates that mGluR5 PAMs facilitate the extinction of drug-seeking behavior in rodent models of addiction and reverse cognitive deficits associated with high levels of methamphetamine intake. The work by Conn and colleagues opens the door to exciting new directions for future research and drug development efforts in neuroscience and neuropsychiatry.


Gass JT, Olive MF. Positive allosteric modulation of mGluR5 receptors facilitates extinction of a cocaine contextual memory. Biol Psychiatry. 2009 Apr 15; 65(8):717-20. Abstract

Reichel CM, Schwendt M, McGinty JF, Olive MF, See RE. Loss of object recognition memory produced by extended access to methamphetamine self-administration is reversed by positive allosteric modulation of metabotropic glutamate receptor 5. Neuropsychopharmacology. 2011 Mar; 36(4):782-92. Abstract

Gass JT, Trantham-Davidson H, Kassab AS, Glen WB, Olive MF, Chandler LJ. Enhancement of extinction learning attenuates ethanol-seeking behavior and alters plasticity in the prefrontal cortex. J Neurosci. 2014 May 28; 34(22):7562-74. Abstract

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