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Fisahn A, Neddens J, Yan L, Buonanno A. Neuregulin-1 modulates hippocampal gamma oscillations: implications for schizophrenia. Cereb Cortex. 2009 Mar 1 ; 19(3):612-8. Pubmed Abstract

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Primary Papers: Neuregulin-1 modulates hippocampal gamma oscillations: implications for schizophrenia.

Comment by:  Kevin Spencer (Disclosure)
Submitted 24 February 2009
Posted 24 February 2009

The recent interest in gamma oscillations as biomarkers of neural circuit function in schizophrenia was spurred by the convergence between neurophysiological experiments in animal models and human post-mortem studies. These studies have found strong evidence that fast-spiking, perisomatic-targeting inhibitory interneurons, which express the calcium-binding protein parvalbumin (PV), are critically involved in the generation of gamma rhythms (Whittington and Traub, 2003), and may also be particularly affected in schizophrenia (Gonzalez-Burgos and Lewis, 2008). It has been thought that this link is strengthened by the reports of abnormalities in several gamma oscillations recorded from schizophrenia patients, compared to healthy individuals. In various studies, the power and/or phase synchronization of gamma oscillations has been found to be reduced in schizophrenia patients (e.g., Brenner et al., 2003; Cho et al., 2006; Ford et al., 2007; Hong et al., 2004; Light et al., 2006; Spencer et al., 2008a, b; Teale et al., 2008).

A recently published study by Fisahn et al. (2009) adds a genetic dimension to the link between gamma oscillations and schizophrenia. Fisahn and colleagues examined how neuregulin-1 (NRG-1) and its ErbB4 receptor influence gamma oscillations in rodent hippocampal slice models. Briefly, NRG-1 is a protein with widespread trophic effects on diverse cell types, including neurons and glia. The ErbB4 receptor is expressed to the greatest degree on interneurons. Genes coding for NRG-1 and ErbB4 have been identified as schizophrenia susceptibility genes (Harrison and Law, 2006), and relationships between NRG-1 and abnormal frontal and temporal cortical function in schizophrenia have been reported (Hahn et al., 2006; Hall et al., 2006). Thus, NRG-1 and ErbB4 are in a position to play a role in interneuron-mediated gamma oscillation abnormalities in schizophrenia.

To elucidate this role, Fisahn and colleagues first examined the effects of NRG-1 on gamma oscillations generated by kainate application in rat hippocampal slices. Perfusion of the  isoform of NRG-1 increased the power of the gamma oscillation by a huge degree, approximately 2000%. NRG-1 had a smaller (~400%) but still significant effect. Neither isoform affected the frequency of the oscillation (~40 Hz). However, NRG-1 had no effect when it was applied without prior induction of gamma oscillation by kainate. Thus, NRG-1 can amplify pre-existing gamma activity, but not induce gamma by itself.

Next, Fisahn and colleagues tested whether the influence of NRG-1 on gamma occurred at the ErbB4 receptor. First, in the rat slices, they pre-treated the slices with a non-specific Erb antagonist, then induced gamma with kainate. The subsequent application of NRG-1 had no effect on gamma power. Since NRG-1 binds to the ErbB3 and ErbB4 receptors, and in the hippocampus ErbB3 is found only on glia, this result suggests that the Erb antagonist blocked NRG-1 action at the ErbB4 receptor.

To further test this hypothesis, Fisahn et al. replicated the NRG-1 effects found in rat slices in hippocampal slices from mice, and then studied the effects of NRG-1 on kainate-induced gamma in ErbB4-knockout mice. In these mice, the increase of gamma power due to NRG-1 application was absent, as in the rats. Furthermore, the power of kainate-induced gamma (without NRG-1) was reduced in the knockout mice compared to wild-type mice. Thus, these experiments demonstrate that NRG-1 and its ErbB4 receptor can play a role in the modulation of gamma rhythmogenesis.

As discussed above, the PV-expressing class of inhibitory interneurons is a key component of the circuitry that generates gamma rhythms. Since Fisahn and colleagues found that NRG-1/ErbB4 affected gamma, they turned to examine whether the ErbB4 receptor might be found on PV interneurons. They found that the populations of cells expressing ErbB4 and PV in the wild-type mice overlapped to some degree: about half of the PV interneurons expressed ErbB4, while about one quarter of the ErbB4-expressing cells also expressed PV. In the ErbB4-knockout mice, the density of PV-expressing cells was reduced by a third. So it is possible that the effects of NRG-1/ErbB4 on gamma were mediated by ErbB4 receptors on PV interneurons. This hypothesis will need to be tested in future studies.

This study is the first to examine the relationships between the product of a susceptibility gene for schizophrenia and the gamma rhythm. The finding that NRG-1 and its ErbB4 receptor influence gamma, possibly through PV-expressing interneurons, sets the stage for a range of follow-up studies in humans and animal models. One caveat is that in the mouse model, the NRG-1 gamma enhancement occurred only for gamma induced by kainate, not by carbachol. (Carbachol induces gamma via activation of AMPA receptors.) While kainate-induced gamma has been important in revealing the mechanisms underlying gamma rhythms, it is unclear to what degree this state resembles in vivo gamma. Nevertheless, the findings of this study are important and raise a number of interesting questions, including:

1. Why does the application of NRG-1 increase gamma power, rather than decrease it? And what might this effect have to do with schizophrenia? As discussed above, most of the gamma abnormalities reported in schizophrenia to date have involved reductions in power and/or phase synchronization. However, positive correlations between phase synchronization and positive symptoms have been reported (Spencer et al., 2004), which can overlap with an overall reduction in the oscillation (Spencer et al., 2008b, and unpublished observations).

2. A related question is what effect does the reduction of PV expression in schizophrenia (Hashimoto et al., 2003; Zhang and Reynolds, 2002) have on gamma, since PV reduction appears to increase, rather than decrease, gamma power (e.g., Vreugdenhil et al., 2003). The results of Fisahn et al. suggest a link between the effects of reduced PV expression and NRG-1/ErbB4 on gamma. And of course, NMDA receptor antagonism can lead to reduced PV expression (Kinney et al., 2006).

3. Recent findings indicate that NMDA receptor antagonism can lead to increases or decreases in gamma power, depending upon the brain region (Cunningham et al., 2006; Ma and Leung, 2000; Pinault, 2008; Roopun et al., 2008). As Fisahn and colleagues note, it will be important to determine whether the effects of NRG-1 and ErbB4 on gamma are also region-specific. Furthermore, it would be important to determine whether NRG-1 and NMDA receptor antagonism have parallel effects on gamma in a given brain region, as suggested by the finding that NRG-1 can suppress NMDA receptor activation (Gu et al., 2005; Hahn et al., 2006).

4. And naturally, how do variants of NRG-1 and ErbB4 influence gamma oscillations (as well as other schizophrenia biomarkers)? Will we find that some variants increase gamma power, while others decrease it? Will these patterns be associated with different symptom clusters? As usual, more research is necessary.

References:

Brenner CA, Sporns O, Lysaker PH, O’Donnell BF (2003). EEG synchronization to modulated auditory tones in schizophrenia, schizoaffective disorder, and schizotypal personality disorder. Am J Psychiatry 160:2238-2240. Abstract

Cho RY, Konecky RO, Carter CS (2006). Impairments in frontal cortical {gamma} synchrony and cognitive control in schizophrenia. Proc Natl Acad Sci USA 103:19878-19883. Abstract

Cunningham MO, Hunt J, Middleton S, LeBeau FEN, Gillies MG, Davies CH, Maycox PR, Whittington MA, Racca C (2006). Region-specific reduction in entorhinal gamma oscillations and parvalbuminimmunoreactive neurons in animal models of psychiatric illness. J Neurosci 26:2767–2776. Abstract

Fisahn A, Neddens J, Yan L, Buonanno A (2009). Neuregulin-1 modulates hippocampal gamma oscillations: implications for schizophrenia. Cereb Cortex 19:612-618. Abstract

Ford JM, Roach BJ, Faustman WO, Mathalon DH (2008). Out-of-synch and out-of-sorts: dysfunction of motor-sensory communication in schizophrenia. Biol Psychiatry 63:736-743. Abstract

Gonzalez-Burgos G, Lewis DA (2008). GABA neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia. Schizophr Bull 34:944–961. Abstract

Gu Z, Jiang Q, Fu AK, Ip NY, Yan Z (2005). Regulation of NMDA receptors by neuregulin signaling in prefrontal cortex. J Neurosci 25:4974-4984. Abstract

Hahn CG, Wang HY, Cho DS, Talbot K, Gur RE, Berrettini WH, Bakshi K, Kamins J, Borgmann-Winter KE, Siegel SJ, Gallop RJ, Arnold SE (2006). Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat Med 12:824-828. Abstract

Harrison PJ, Law AJ (2006). Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biol Psychiatry 60:132–140. Abstract

Hashimoto T, Volk DW, Eggan SM, Mirnics K, Pierri JN, Sun Z, Sampson AR, Lewis DA (2003). Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci 23:6315-6326. Abstract

Hong LE, Summerfelt A, McMahon R, Adami H, Francis G, Elliott A, Buchanan RW, Thaker GK (2004). Evoked gamma band synchronization and the liability for schizophrenia. Schizophr Res 70:293-302. Abstract

Kinney JW, Davis CN, Tabarean I, Conti B, Bartfai T, Behrens MM (2006). A specific role for NR2A-containing NMDA receptors in the maintenance of parvalbumin and GAD67 immunoreactivity in cultured interneurons. J Neurosci 26:1604-1615. Abstract

Light GA, Hsu JL, Hsieh MH, Meyer-Gomes K, Sprock J, Swerdlow NR, Braff DL (2006). Gamma band EEG oscillations reveal neural network cortical coherence dysfunction in schizophrenia patients. Biol Psychiatry 60:1231-1240. Abstract

Ma J, Leung L-WS (2000). Relation between hippocampal γ waves and behavioral disturbances induced by phencyclidine and methamphetamine. Behav Brain Res 111:1-11. Abstract

Pinault D (2008). N-methyl d-aspartate receptor antagonists ketamine and MK-801 induce wake-related aberrant [gamma] oscillations in the rat neocortex. Biol Psychiatry 63:730–735. Abstract

Roopun AK, Cunningham MO, Racca C, Alter K, Traub RD, Whittington MA (2008). Region-specific changes in gamma and beta2 rhythms in NMDA receptor dysfunction models of schizophrenia. Schizophr Bull 34:962–973. Abstract

Spencer KM, Niznikiewicz MA, Shenton ME, McCarley RW (2008a). Sensory-evoked gamma oscillations in chronic schizophrenia. Biol Psychiatry 63:744-747. Abstract

Spencer KM, Nestor PG, Perlmutter R, Niznikiewicz MA, Klump MC, Frumin M, Shenton ME, McCarley RW (2004). Neural synchrony indexes disordered perception and cognition in schizophrenia. Proc Natl Acad Sci USA 101:17288-17293. Abstract

Spencer KM, Salisbury DF, Shenton ME, McCarley RW (2008b). Gamma-band auditory steady-state responses are impaired in first episode psychosis. Biol Psychiatry 64:369-375. Abstract

Teale P, Collins D, Maharajh K, Rojas DC, Kronberg E, Reite M (2008). Cortical source estimates of gamma band amplitude and phase are different in schizophrenia. NeuroImage 42:1481–1489. Abstract

Vreugdenhil M, Jefferys JG, Celio MR, Schwaller B (2003). Parvalbum indeficiency facilitates repetitive IPSCs and gamma oscillations in the hippocampus. J Neurophysiol 89:1414-1422. Abstract

Whittington MA, Traub R (2003). Inhibitory interneurons and network oscillations in vitro. Trends Neurosci 26:676-682. Abstract

Zhang ZJ, Reynolds GP (2002). A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia. Schizophr Res 55:1-10. Abstract

View all comments by Kevin Spencer

Primary Papers: Neuregulin-1 modulates hippocampal gamma oscillations: implications for schizophrenia.

Comment by:  Richard Deth
Submitted 24 February 2009
Posted 25 February 2009
  I recommend this paper

Interestingly, dopamine D4 receptors mediate neureglin-1 effects on LTP, and D4 receptor variants have also been shown to influence gamma frequency power.

References:

Kwon OB, Paredes D, Gonzalez CM, Neddens J, Hernandez L, Vullhorst D, Buonanno A. Neuregulin-1 regulates LTP at CA1 hippocampal synapses through activation of dopamine D4 receptors. Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15587-92. Abstract

View all comments by Richard Deth