Neuregulin signaling, cortical circuitry development and schizophrenia
Introduction
Schizophrenia is a severe mental illness that affects approximately 1% of the population worldwide. Genetic factors play a major role in the development of schizophrenia, with an estimated heritability of around 80% [1]. In addition, environmental stressors seem to be key determinants in the initiation of the disorder. Schizophrenia is formally diagnosed by the presence of three distinct symptom clusters: positive (e.g. delusions, hallucinations), negative (e.g. apathy, social withdrawal) and cognitive (e.g. attention, working memory). Positive symptoms are the most dramatic manifestations of the disease, but cognitive deficits are perhaps the most distinctive features. Individuals that suffer from schizophrenia have important deficits in memory, attention and executive function, and some of these disturbances appear before the onset of psychosis [2]. Milder cognitive deficits are often present in unaffected relatives [3], which reinforce the view that cognitive impairment lies at the core of the disorder. Although the pathophysiological mechanism underlying these cognitive disturbances has yet to be determined, recent work indicates that abnormal inhibitory function and a concomitant disruption of synchronized oscillatory activity in the cerebral cortex may play an important role in this process [4, 5, 6, 7•].
Several lines of evidence suggest that schizophrenia arises as a consequence of abnormal brain development [8, 9]. According to this view, genes linked to the disease encode for proteins that play a major role in the development of specific brain circuitries, most notably in the cerebral cortex. This would lead to a suboptimal conformation of cortical circuitries that is susceptible to deteriorate beyond normal performance levels in the presence of additional environmental factors, such as drug abuse or stress. Consequently, unraveling the mechanisms underlying schizophrenia depends, at least in part, on characterizing the function that risk genes may play in the development of the cerebral cortex.
Genetic studies over the past few years have found a strong association between the gene encoding for Neuregulin-1 (NRG1) and schizophrenia. Since Stefansson et al. [10] identified NRG1 as a candidate gene for the disorder, numerous studies have obtained supporting evidence for this hypothesis [11]. The recent identification of the NRG1 receptor ErbB4 as an additional candidate risk gene for schizophrenia has added support to the hypothesis that this signaling pathway plays an important role in the pathophysiology of the disorder [12••, 13, 14, 15]. These findings have fueled research in this area, most notably in the search for a plausible biological mechanism that could explain their involvement in the disease process. Although NRG1 and ErbB4 have been implicated in multiple developmental events, recent work has focused on the function of these genes in the wiring of the cerebral cortex. Here, we summarize recent findings illustrating how abnormal Nrg1/ErbB4 signaling disrupts GABAergic function in the cerebral cortex, the main topic of the present review. These results are also analyzed in the context of recent studies that highlight the relevance of cortical interneurons in cognitive function, and their possible implication in the pathophysiology of schizophrenia.
Section snippets
Neuregulin-1 and its receptors
NRG1 is a member of a family of four genes encoding for structurally related proteins characterized by an EGF-like domain that mediates their interaction with ErbB receptor tyrosine kinases [16]. Alternative splicing of NRG1 generates over 30 isoforms, which can be grouped into six types of proteins with different structural and functional personalities [17•]. Most NRG1 isoforms contain an immunoglobulin (Ig)-like domain and are synthesized as single-pass transmembrane molecules with the
ErbB4 expression in the developing cerebral cortex
ErbB4 is probably the most abundant neuregulin receptor in the mouse forebrain [20, 21], but its cellular distribution has been a matter of debate until very recently. Thus, while ErbB4 expression has been largely attributed to GABAergic neurons in the embryonic telencephalon [22, 23], ErbB4 receptors have been associated with both glutamatergic pyramidal cells and GABAergic interneurons in the postnatal cortex [20, 22, 24, 25, 26, 27, 28, 29]. This apparent discrepancy has led to contradictory
Wiring of inhibitory circuitries by Nrg1 and ErbB4
As summarized above, ErbB4 seems to be expressed by the same population of interneurons at both embryonic and postnatal stages, which suggests that neuregulin signaling may regulate different aspects of their development. Consistent with this view, Nrg1 and ErbB4 have been shown to regulate the migration of some interneurons derived from the medial ganglionic eminence (MGE), a transitory proliferative region in the subpallium that is the main source of PV+ interneurons [23]. Immature
Neural circuitry disruption in schizophrenia
The experiments summarized above demonstrate that ErbB4 mediates consecutive functions of Nrg1 in the establishment of specific inhibitory circuitries in the neocortex and hippocampus of mice. Depending on the timing of the perturbation, loss of ErbB4 signaling may disrupt inhibitory circuitries in different ways. Thus, early loss of ErbB4 reduces the number of interneurons that reach the cortex, while late disruption of Nrg1/ErbB4 signaling impairs synapse formation. In addition, Nrg1
New perspectives for treatment?
It is presently unclear how genetic variation in NRG1 and ERBB4 may predispose to schizophrenia. Several studies have suggested that risk haplotypes may increase NRG1/ERBB4 signaling in adult humans [53, 54]. At this point, however, interpretation of these studies is problematic, because we do not know whether the reported defects are directly caused by the risk haplotypes, or a consequence of compensatory mechanisms which are ongoing in the patient brain. In addition, recent studies in animal
A look ahead
There are many important questions that remain to be addressed on the precise role of neuregulin signaling in the organization of inhibitory circuitries and its involvement in schizophrenia. For example, it is unclear whether ErbB4 is present in the dendrites and axons of precisely the same population of interneurons. It is possible, for example, that postsynaptic ErbB4 expression is restricted to basket cells, while presynaptic ErbB4 receptors concentrate primarily on chandelier cells. Solving
Note added in proof
While this review was in press a manuscript by Ting and colleagues [64] was published. In this study, the authors found that in vivo deletion of ErbB4 in parvalbumin-positive interneurons led to deficits in the excitatory inputs receive these cells, and that Nrg1 increases the number, size, frequency and amplitude of mEPSCs in vitro. Together, these results add support to the idea that Nrg1/ErbB4 signalling is important for excitatory synaptogenesis in interneurons.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We are grateful to Isabel del Pino and Cristina García-Frigola for their comments on the manuscript, and members of the Borrell, Marín and Rico labs for helpful discussions. We apologize to colleagues whose work is not cited in this review. Regrettably, space was too limited to cite all significant original articles. Work in our laboratory is supported by grants from Spanish Ministry of Science and Innovation (MICINN) SAF2010-21723 and Fundación Alicia Koplowitz to BR, and MICINN SAF2008-00770,
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2020, Comprehensive PsychiatryAltered inhibition and excitation in neocortical circuits in congenital microcephaly
2019, Neurobiology of DiseaseCitation Excerpt :Since cortical processing relies on the fine-tuned interplay between excitation and inhibition, healthy brains exhibit a tight control of E/I ratio in all cortical areas even after perturbations (House et al., 2011; Xue et al., 2014). This control is usually ensured by several regulators of E/I adjustment (House et al., 2011; Lin et al., 2008; Rico and Marín, 2011; Xue et al., 2014). Our results in Cdk5rap2 mutants argue for an impaired E/I set point regulation as putatively caused by improper expression or targeting of molecules that control synaptic specificity.
An essential role for neuregulin-4 in the growth and elaboration of developing neocortical pyramidal dendrites
2018, Experimental NeurologyCitation Excerpt :Likewise, numerous studies on NRG2 and NRG3 have revealed that they participate in synaptogenesis, synaptic function and aspects of neuronal development (Bartolini et al., 2017; Lee et al., 2015; Vullhorst et al., 2015). Importantly, the Nrg1, Nrg2, Nrg3, ErbB3 and ErbB4 genes have been identified as susceptibility genes for schizophrenia, depression and bipolar disorder (Mei and Nave, 2014; Rico and Marin, 2011) and numerous genetic and functional studies have directly implicated the Nrg1, Nrg2, Nrg3 and ErbB4 genes in the development of psychotic behaviour (Hayes et al., 2016; O'Tuathaigh et al., 2007, 2010; Shamir et al., 2012; Yan et al., 2017). Although much less work has been done on the latest neuregulins to be identified, NRG5 and NRG6, both are highly expressed in brain (Kanemoto et al., 2001; Kinugasa et al., 2004).
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2018, Comprehensive Toxicology: Third Edition