Neuregulin 1: an intriguing therapeutic target for neurodevelopmental disorders

ABSTRACT Neurodevelopmental psychiatric disorders including schizophrenia (Sz) and attention deficit hyperactivity disorder (ADHD) are chronic mental illnesses, which place costly and

painful burdens on patients, their families and society. In recent years, the epidermal growth factor (EGF) family member Neuregulin 1 (NRG1) and one of its receptors, ErbB4, have received

considerable attention due to their regulation of inhibitory local neural circuit mechanisms important for information processing, attention, and cognitive flexibility. Here we examine an

emerging body of work indicating that either decreasing NRG1–ErbB4 signaling in fast-spiking parvalbumin positive (PV+) interneurons or increasing it in vasoactive intestinal peptide

positive (VIP+) interneurons could reactivate cortical plasticity, potentially making it a future target for gene therapy in adults with neurodevelopmental disorders. We propose preclinical

studies to explore this model in prefrontal cortex (PFC), but also review the many challenges in pursuing cell type and brain-region-specific therapeutic approaches for the NRG1 system.

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Neurodevelopmental disorders including schizophrenia (Sz) and attention deficit hyperactivity disorder (ADHD) are chronic mental illnesses. For years, scientists have sought more effective

treatment options for improving the cognitive outcomes in patients with Sz. The trophic factor Neuregulin 1 (NRG1, also called heuregulin1 or neu differentiation factor) activates signaling

cascades, which regulate inhibitory neural processes important for executive functions, such as attention and working memory, which are impaired in Sz1,2. NRG1 is the best characterized of a

four-member gene family (NRG1-NRG4) that all share an epidermal growth factor (EGF)-like domain with ErbB receptor binding activity (Fig. 1). With 33 exons, NRG1 isoform diversity is

appreciable—most isoforms are synthesized as transmembrane (TM) pro-proteins that undergo proteolytic cleavage liberating a bioactive extracellular or ectodomain (ED) via a process called

‘ED shedding.’ Binding of the liberated NRG1 ED to the ErbB family of receptors stimulates signaling cascades involved in learning, memory, and other higher brain functions. Association

studies link variants in the NRG1 gene with some of the cognitive deficits seen in Sz (reviewed in ref. 3); however, none meet genome wide significance for conferring an increased risk for

the disorder4,5,6. The ErbB4 receptor subtype, in particular, plays a key role in the inhibitory functions of NRG1 in the CNS7,8,9,10,11. There is an extensive literature on the role of

NRG1–ErbB4 signaling in early cortical development12,13,14,15 but see also ref. 16. In the following sections, we critically re-evaluate over two decades of research on the function of NRG1

in the mature central nervous system (CNS). We place particular emphasis on the complex role of NRG1–ErbB4 signaling in local circuit inhibitory neurons on cortical function and plasticity.

We also examine the intrinsic and extrinsic factors regulating ED shedding, as this step holds the key to controlling NRG1 bioavailability. Finally, we develop a model for treating adults

with Sz via gene therapies targeting NRG1/ErbB4 signaling in local circuit interneurons. Although much data support this model, we discuss the many challenges currently hindering translation

of these types of therapeutic approaches. CRITICAL PERIODS OF CORTEX DEVELOPMENT AND NEURODEVELOPMENTAL DISORDERS Neurodevelopmental psychiatric disorders such as Sz typically emerge in

late adolescence or early adulthood. This developmental epoch is considered to be a ‘critical period’ for maturation of prefrontal cortex (PFC), analogous to the postnatal timeframes defined

for visual and other sensory systems17,18. Critical periods are also a time of heightened synaptic remodeling and integration of inhibitory interneurons into local neural circuits in

cortex19(Fig. 2a). The best studied local circuit connects three main classes of interneurons (parvalbumin positive, PV+; somatostatin positive, SST+; and vasoactive intestinal peptide

positive, VIP+) with excitatory pyramidal neurons, which are the principal output cells of cortex20 (Fig. 2b). During critical periods synaptic connections between interneurons and principal

neurons are sculpted via mechanisms including pruning of dendritic spines on pyramidal cells and strengthening of excitatory synapses on PV+ and VIP+ classes of interneurons11,18,21,22. The

coordinated activity of local circuit neurons plays a pivotal role in generating rhythmic patterns of neural activity in mature cortex. Fast-spiking PV+ basket cells, in particular, are

crucial for the entrainment of gamma oscillations23. Oscillations in the gamma range (30–90 Hz) are associated with higher brain functions impaired in neurodevelopmental disorders such as

working memory and attention24. Patients with Sz exhibit gamma oscillation abnormalities, which underscores the relevance of local circuit function as a therapeutic outcome25,26,27. The

extensive synaptic remodeling that occurs during critical period development decreases excitatory drive in cortex while enhancing inhibitory tone. As a result, neural circuits in cortex are

less plastic after critical period closure (Fig. 2a). Additionally, other neural and genetic remodeling processes (e.g., myelination, perineuronal nets, and DNA methylation) come into

play18. Along with increased inhibitory tone, these mechanisms are thought to constrain cortical plasticity, in effect limiting the learning and memory gains achievable with aging.

Presumably, a persistent reduction in PFC plasticity in adulthood contributes to the failure of current therapies to rehabilitate the cognitive deficits associated with Sz28. An exciting

body of work in the visual system points to a set of local circuit neuron-based manipulations that can be performed after critical period closure to reactivate cortical plasticity (Fig. 2c).

Initial findings revealed that manipulations that reduce excitatory input onto fast-spiking PV+ basket cells are effective22. Subsequent studies using transgenic and viral tools showed that

either activating VIP+ interneurons or silencing SST+ interneurons represent other ways to disinhibit pyramidal cells and re-evoke plasticity29. Likewise, recent evidence indicates that

manipulating NRG1–ErbB4 signaling in fast- spiking PV+ basket cells offers an additional option for overcoming reduced cortical excitability30. As discussed below, this and related findings

from studies in VIP+ interneurons suggest that NRG1–ErbB4 signaling in interneurons could be poised to provide a tractable target for re-evoking cortical plasticity in PFC11. CRUCIAL ROLE OF

NRG1 IN LOCAL CIRCUIT DEVELOPMENT AND CORTICAL PLASTICITY Several lines of evidence link NRG1 and ErbB4 with local circuit interneuron function. Foremost is the finding showing that a

recombinant peptide corresponding to the EGF-like domain of NRG1 stimulates activity-dependent release of the inhibitory transmitter GABA31. This discovery set the stage for subsequent work

demonstrating that the NRG1 EGF-like domain regulates not only gamma oscillations1, but also a host of related neural and behavioral phenomena including pyramidal cell excitability2, seizure

activity32,33,34, synaptic plasticity8,9,33,35, and anxiety-like behavior36. The effects were shown in all cases to hinge on expression of ErbB4 receptors on PV+ neurons. The ability of the

EGF-like domain peptide to suppress seizure activity and long-term synaptic potentiation (LTP) also implicates NRG1 in homeostatic mechanisms controlling excitatory and inhibitory (E/I)

balance in neural circuits9,34. Within cortex and hippocampus, ErbB4 receptors are predominantly expressed in interneurons, but also present in axonal projections of dopamine (DA) neurons as

well as in oligodendrocytes7,10,37. As observed for PV+ basket cells, the vast majority of VIP+ interneurons in cortex prominently express ErbB4, whereas expression of the NRG1 receptor in

cortical SST+ interneurons is sparse10,11,37,38 (Fig. 2c). Knockout of ErbB4 selectively in VIP+ interneurons abolishes the synchronized firing of fast-spiking PV+ and pyramidal neurons11.

Thus, NRG1 activated signaling regulates the entrainment of oscillations in cortex via its actions on VIP+ interneurons in addition to its effects on fast-spiking PV+ basket cells. Studies

with DA neuron-specific ErbB4 knockout mice indicate that dopaminergic expression of this NRG1 receptor is important for working memory; however, it is not yet clear if the mechanism

involves modification of synchronized activity39. Recent work indicates that NRG1 signaling also modulates the phase locking (neural synchrony) of local field potentials in ventral

hippocampus and PFC40. This is relevant for neurodevelopmental disorders as ventral hippocampus-prefrontal synchrony in the theta and delta frequency ranges positively correlates with

performance on the 5-choice serial reaction time test (5-CSRTT), which is a well-accepted task of attention40,41. Studies with ErbB4 ATP binding site mutant knockin mice indicate that ErbB4

receptors in ventral hippocampus and PFC play a role in performance on the 5-CSRTT as well as in ventral hippocampal-prefrontal synchrony40. These studies also showed that ErbB4 constitutive

knockout mice (heart rescued) exhibit reduced hippocampal-prefrontal synchrony and deficits in attention40. Note, however, that another group reported no deficits in the performance of the

ErbB4 constitutive knockout mice (heart rescued) on the 5-CSRTT relative to controls42. Other electrophysiological studies indicate, however, that interneuronal NRG1–ErbB4 signaling

regulates neural synchrony in cortex1,43,44. Although NRG1 enhances activity-dependent GABA transmission in cortex31, electrophysiological studies indicate that ErbB4 signaling in

interneurons largely promotes maturation of glutamatergic inputs onto PV+ and VIP+ interneurons11,30,45. Consistent with this idea, ErbB4 receptors localize near excitatory inputs onto

somatodendritic regions of interneurons2,37,46,47. Molecular studies suggest that NRG1–EGF-like domain binding stimulates ErbB4 receptor phosphorylation, which results in activation of a set

of downstream signaling cascades (e.g., PI3 kinase/AKT, ERK, and perhaps others) (reviewed in ref. 48). Several studies indicate that ErbB4 signaling in interneurons stimulates

incorporation of AMPA receptors into postsynaptic membranes, which is an established mechanism for potentiating excitatory transmission49,50,51. Two studies reported that ErbB4 signaling in

interneurons preferentially regulates NMDA receptors. However, one study examined responses in a type I NRG1 transgenic mouse in which levels of ErbB4 in cortical interneurons are

significantly downregulated52; the other study investigated the actions of NRG253. Interaction of ErbB4 with PSD95, a postsynaptic scaffolding protein found at mature glutamatergic synapses,

could also play a role in the mechanism as NRG1 signaling increases PSD95 levels near excitatory synapses on cortical interneurons in culture50,54,55,56. Altogether, these findings suggest

that ErbB4 signaling regulates the molecular composition of excitatory synapses in interneurons via diverse mechanisms. NRG1–ErbB4 signaling increases the firing of VIP+ and PV+

interneurons, in addition to promoting maturation of excitatory synapses on these cells. Although, the mechanism is not fully understood, the effect of ErbB4 signaling in PV+ interneurons is

a reduction in both activity-dependent and spontaneous firing of pyramidal cells2,45. In contrast, ErbB4 signaling in VIP+ neurons regulates the synchronous firing of cortical pyramidal

cells11. As discussed above, reduced pyramidal cell excitability is a key mechanism in critical period closure, as well as in the subsequent maintenance of reduced cortical plasticity (Fig.

2b). Intriguingly, a recent study on visual cortex showed that functional recovery of cortical plasticity in adults can be achieved by blocking NRG1 stimulation of ErbB4 receptors in PV+

neurons30. Hence, inhibiting ErbB4 activation in PV+ cells could be a viable alternative to the manipulations mentioned above for disinhibiting pyramidal cells after critical period

closure22,29. Likewise, restoration of ErbB4 in VIP+ interneurons of the V1 area of visual cortex was found to rescue the cortical activity and visual performance deficits of mice with

targeted deletion of ErbB4 in VIP+ cells11. These findings raise the intriguing possibility that selective targeting of NRG1 activation of ErbB4 in PV+ or VIP+ interneurons could also

potentially improve PFC plasticity in adults. DEVELOPING NRG1-BASED GENE THERAPIES FOR INCREASING CORTICAL PLASTICITY IN ADULTS Gene therapy of diseases of the CNS is an emerging technology

offering the potential to manipulate the expression of specific molecules in select neural circuits by stereotactic delivery of recombinant viruses into various brain nuclei. Although

invasive, recently completed Phase I and II clinical trials for Parkinson’s and Alzheimer’s diseases have demonstrated the safety of this therapeutic approach57,58. As discussed above,

several lines of evidence from studies on primary sensory cortices support the potential efficacy of manipulating NRG1–ErbB4 signaling in local circuit interneurons for reactivating

plasticity in mature cortex11,29,30,51. Moreover, these studies show that NRG1–ErbB4 signaling in PV+ and VIP+ local circuit interneurons regulates signal detection, noise filtering,

information encoding, and rhythmic brain activity—all of which are critical for performance of executive functions like attention and working memory. In theory, therefore, these findings

would seem to suggest that NRG1 and ErbB4 could be promising targets for gene therapy of neurodevelopmental disorders such as Sz. This idea is supported in principal by recent work showing

that transgenic reinstatement of NRG1–ErbB4 signaling in adulthood can rescue some deficits in cortical GABA transmission caused by knockout of ErbB4 during early development59. To justify

consideration as a therapeutic strategy, however, preclinical studies are needed to validate that manipulations of NRG–ErbB4 signaling in local circuit neurons can re-evoke cortical

plasticity in higher order association area like PFC. In the following sections, we develop a circuit-based model for testing whether manipulating NRG1–ErbB4 signaling can reactivate

plasticity of adult PFC. An advantage of circuit-based models is that they provide a framework for investigating alternate targets and signaling pathways60. The model developed here takes

advantage of evidence linking local circuit interneuron with mechanisms that can reactivate excitability in cortex after critical period closure22,29,30,61. We propose two strategies for

testing this model that focus on selectively increasing or decreasing ErbB4 signaling in PV+ or VIP+ interneurons, respectively. They explore the potential of targeting ErbB4 signaling local

circuit interneurons as it is not yet known whether manipulating ErbB4 in other cell types (DA neurons or oligodendrocytes) can reactivate cortical plasticity after critical period closure.

Neither strategy is intended to rescue any potential disease-related abnormalities in the NRG1 gene or anomalies its expression. The main driver of these strategies is the evidence (1)

showing that cell-specific manipulation of ErbB4 receptors in either PV+ and VIP+ interneurons provides a means of tuning excitability of mature cortex11,30,45,51, and (2) indicating the

differential cellular and subcellular distribution of NRG1 isoforms62,63,64,65,66 (Fig. 3). The model generates a number of testable hypotheses regarding the role of different NRG1 isoforms

in maintaining the strength of glutamatergic synapse on PV+ and VIP+ interneurons in cortex. Regional and cellular aspects of the model could be tested in either wild-type mice or mouse

models of Sz67 via stereotactic injection of a recombinant adeno-associated virus (AAV) or lentivirus (LV) carrying a floxed cDNA or siRNA into PFC of adult transgenic mice in which CRE

expression is conferred via a cell-specific promoter. AAVs and LVs are frequently the vectors of choice for gene therapy due to their stable long-term expression (up to years) and low risk

of pathogenesis or cytotoxicity68,69. Use of transgenic CRE mice would enable testing of cell-type-specific predictions of the local circuit interneuron model. Regional specificity is

critical because both the NRG1 and ErbB4 genes are expressed in a variety of cortical and subcortical brain regions7,10,15,70. Undesired side-effects resulting from global manipulation of a

particular isoform in brain, even if cell-type-specific, could overshadow any potential benefits on prefrontal cortical plasticity. In support of this possibility, Sz-relevant behavioral and

neuronal abnormalities were detected in transgenic mice that overexpress either the full length or just the bioactive ED of type I NRG1 in principal neurons throughout the brain52,71,72,73.

Behavioral and neural deficits were also detected in transgenic mice with cell specific but brain-wide upregulation of other NRG1 isoforms (Table 1). For similar reasons, the ErbB2

monoclonal antibodies (Trastuzumab) that are used to treat Her2+ breast cancer, or the molecules (e.g., recombinant NRG1β and anti-ErbB4 antibodies) that are currently in development for

heart disease and cancer might not be useful for neurodevelopmental disorders74,75. Moreover, systemic use of these agents could result in ‘off target’ complications due to, for example, the

mitogenic effects of NRG1–ErbB signaling on the heart. REDUCE NRG1 ED AVAILABILITY AT EXCITATORY SYNAPSES ON PV+ BASKET CELLS NRG1 signaling via ErbB4 maintains high levels of excitatory

input onto fast-spiking PV+ basket cells, which is a key mechanism for dampening pyramidal cell activity in mature cortex30,45. One approach to increasing plasticity in adult PFC would

therefore be to minimize NRG1 ED levels in the vicinity of excitatory synapses on PV+ basket cells. Several lines of evidence indicate that type III NRG1 isoforms, in particular, play an

important role in maintaining excitatory input to fast-spiking PV+. For example, increased inhibition and reduced pyramidal neuron plasticity is detected in mice carrying a transgene that

drives expression of type III cDNA in excitatory neurons76. In addition, reduced levels of type III NRG1 in excitatory neurons decreases glutamate transmission from these terminals77.

Furthermore, the EGF-like domain of type III localizes to presynaptic terminals based on recombinant protein expression studies64,66, whereas type I and type II NRG1 isoforms localize to

somatodendritic regions63,66 (Fig. 3). Interestingly, BACE1 cleavage is critical for localization of the type III EGF-like domain in presynaptic terminals of excitatory neurons63,64,66.

BACE1 is a transmembrane aspartyl protease that is most active in organelles with low lumenal pH such as the Golgi or early endosomes. Cleavage of type III pro-protein can be blocked by cell

permeable inhibitors of BACE1, but not by membrane impermeant inhibitors of the enzyme suggesting that the proteolytic step could occur in the Golgi62. A protein fragment containing the

EGF-like domain and upstream cysteine-rich domain (CRD) of type III is transported to axon terminals following ED cleavage in the stalk segment of the pro-protein62,66. Indeed, one study

showed that inclusion of the EGF-like domain is necessary for presynaptic localization of the BACE1-cleaved type III fragment, highlighting the possibility that interaction with

trans-synaptic ErbB4 receptors could play a role in the anchoring mechanism66. For single transmembrane NRG1 isoforms like type I and type II, sheddase cleavage in the linker liberates the

EGF-like domain containing N-terminus (Fig. 1). Release of the bioactive EGF-like domain from cells can stimulate nearby ErbB receptors via either a paracrine or autocrine signaling

mechanism. Extensive work, however, suggests that the EGF-like domain of type III isoforms remains membrane associated after sheddase cleavage due to the presence of the CRD which functions

as a TM segment78,79 (Fig. 1). In some contexts, cell-attached configurations of the NRG1–EGF-like domain display bioactivity80. The recent discovery of additional BACE1 and ADAM17 cut sites

between the CRD and EGF-like domains, however, indicates that type III isoforms might also be able to signal via a shedding-dependent mechanism81 (Fig. 1). Silencing of type III in

pyramidal neurons would be expected to preempt accumulation of the CRD-linked EGF-like domain at excitatory inputs onto fast-spiking PV+ basket cells. If the model shown in Fig. 4 is

correct, this strategy should attenuate ErbB4 activation at these synapses, which should result in an increase in pyramidal cell activity and cortical plasticity. Type III silencing can be

achieved by stereotactic injection of a recombinant AAV carrying a floxed type-III-specific short-interfering RNA (siRNA) into PFC of adult mice harboring a CRE transgene driven by a

promoter expressed only in pyramidal cells in cortex such as Thy182 (Fig. 4). There are a couple of features of type III transcripts that can be exploited in creating an isoform-selective

reduction in type III via gene silencing strategies with siRNA. First, transcripts for type III derive from a unique promoter, whereas different promoters are used for transcribing other

NRG1 isoforms83. Secondly, the exon encoding the CRD is found only in type III transcripts. Increased type III mRNA in PFC is associated with the HapICE risk haplotype for Sz found in the

NRG1 gene84,85,86. If silencing type III in pyramidal cells in adult mice increases prefrontal plasticity and improves performance on tests of executive functions, then this strategy could

potentially be a viable therapeutic approach to explore. In addition to contacting local circuit interneurons via axon collaterals, PFC pyramidal cells project to a range of more distant

cortical and subcortical targets that regulate cognitive and emotional processing, action selection, and reward behavior87. The consequences of type III KD on these behaviors are unknown,

but as with any effects on local circuits, would presumably depend on ErbB4 expression in neurons targeted by these PFC projections. In this regard, there could be effects on regulation of

fear and anxiety because ErbB4 expression is densest in the intercalated nucleus and medial region of the amygdala10. On the other hand, the effects of manipulating NRG1 could be attenuated

as PFC projections appear to primarily target the anterior basal nucleus88. Another question is whether NRG1 type III KD could impact NRG3, which is also present in pyramidal axon terminals,

in relatively close apposition to postsynaptic ErbB4 receptors66,89. Compared to NRG1, NRG3 is a much weaker (>104-fold lower) agonist of ErbB4 tyrosine kinase activity89. Studies of KO

mice indicate that NRG3 functions in excitatory terminals to promote synapse formation on interneurons, and to suppress glutamate release—however, neither function requires ErbB489,90.

Although none of the available data suggests that the functions of type III NRG1 and NRG3 are interdependent66,89,90,91,92,93, much remains to be learned about these different NRGs in local

circuits. Below, we propose an alternate strategy for reactivating plasticity in adult PFC by manipulating NRG1–ErbB4 signaling in VIP+ interneurons. INCREASE NRG1 ED AVAILABILITY AT

EXCITATORY SYNAPSES ON VIP+ INTERNEURONS VIP+ interneurons enhance signal detection and noise filtering during arousal by modulating the basal excitability of pyramidal neurons—this

translates into an improved ability of cortex to encode relevant new information11,61. In visual cortex at least, stimulating VIP+ neuronal activity is sufficient to disinhibit pyramidal

cells, which is the central mechanism underlying reactivation of cortical plasticity18,29 (Fig. 2c). Furthermore, optogenetic studies indicate that selectively activating VIP+ interneurons

dramatically improves performance on working memory tests61. Knockout of ErbB4 receptors selectively in VIP+ interneurons abolishes the synchronized firing of fast-spiking PV+ and pyramidal

neurons in visual cortex11. Stimulating ErbB4 in VIP+ interneurons therefore potentially represents an alternative strategy for reactivating plasticity in PFC11 (Fig. 5). VIP+ interneurons

receive glutamatergic, cholinergic, serotonergic afferents from subcortical and other cortical areas94,95,96; however, ErbB4 receptors seem to only strengthen glutamatergic input onto these

cells11. If the model shown in Fig. 5 is correct, pyramidal cell disinhibiton could be accomplished by microinjecting PFC of mice harboring a VIP+ promoter-driven CRE transgene with a

recombinant AAV carrying a floxed cDNA encoding a sheddable isoform of NRG1, or the corresponding ED. Reasonable candidates include the type I and II isoforms as they are abundant in

cortical GABAergic neurons64, and like ErbB4 receptors, these isoforms localize to neuronal somatodendritic compartments63,65,66 (Fig. 3). Type II could be a good first choice because

glutamate stimulation promotes shedding of this isoform in transfected cortical neurons63. Additionally, the benefit of upregulating type I isoforms in VIP+ neurons is debatable. On the one

hand, this isoform seems to undergo constitutive shedding, which could be advantageous for gene therapies designed to boost ErbB4 activity78,79,97,98. Nevertheless, concerns are raised by

reports of upregulated type I NRG1 in cortex of patients with Sz99,100,101. However, the effect of upregulating type I exclusively in interneurons has yet to be examined. Two studies have

looked at mechanisms regulating NRG1 shedding from neurons63,66. One study of transfected neurons found that ADAM17 and protein kinase C (PKC) are required for neural activity-stimulated

shedding of the bioactive ED63. More detailed mechanistic studies in non-neuronal cells show that PKC stimulates ED shedding (1) by increasing cell surface levels of ADAM17, and (2) by

phosphorylating key residues in the intracellular domain (ICD) of NRG1102. These studies also showed that PKCδ-mediated phosphorylation of serine residue 286 in the NRG1 ICD is critical for

ADAM17 cleavage103,104. ICD phosphorylation is proposed to initiate conformational changes in the NRG1 polypeptide that are relayed through the plasma membrane, and ultimately increase

accessibility of the ADAM17 cleavage site in the ED105,106. Like NRG1, many proteins expressed in brain are substrates of ADAM17 or PKC (e.g., voltage gated Na+ channels, amyloid precursor

protein and Notch/Delta), so upregulation of either enzyme would likely produce “off-target” side-effects107,108,109,110. On the other hand, knowledge of mechanisms promoting NRG1 shedding

could be useful in the design of ED shedding-prone variants carrying mutations mimicking phosphorylation of key PKC sites in the ICD. CONCLUDING REMARKS AND FUTURE PERSPECTIVES Here we

review data implicating NRG1–ErbB4 signaling in cortical plasticity and executive functions. We also explore the possibility of remediating cognitive and executive function deficits

associated with Sz using gene therapy directed at NRG1–ErbB4 signaling in local circuits neurons in PFC. The therapeutic model that we develop takes advantage of cutting-edge information on

local circuit mechanisms for reactivating excitability in cortex after critical period closure22,29,30. One advantage of this circuit-based approach is that it provides a framework for

investigating alternate targets or signaling pathways. Another option would be to manipulate ErbB4 either in PV+ or VIP+ interneurons. Ideally, the biology underlying the illness will

dictate which brain area should be targeted111. Justifications for targeting PFC include its well-established role in executive functions (e.g., cognitive flexibility, forward planning, and

inhibition), which are significantly impaired in patients with Sz112,113. Further, stronger activation of PFC positively correlates with better functional outcomes for patients with Sz114.

However, the primary neuroanatomical deficits of Sz are not well established. Indeed, meta-analyses suggest that in addition to PFC, improved outcomes correlate with increased resting-sate

activity in several other brain regions (e.g., left hippocampus, superior temporal sulcus, and anterior and posterior cingulate cortex)114,115,116,117. It will be important to compare the

relative efficacy of gene therapies injected into PFC versus these other fronto-limbic areas in improving executive functions. Postmortem neuropathological findings suggest that alterations

in the cellular organization of cortex could be associated with Sz. Abnormalities reported range from a decreased density of inhibitory neurons to an increased number of proinflammatory

cytokine-secreting microglia118. It is unclear whether these types of abnormalities would limit or accelerate possibilities for neural rehabilitation via the strategies proposed. Even if the

proposed preclinical studies validate the promise of these novel approaches, there are a number of issues that would still need to be addressed before gene therapy for Sz could be

considered a near term possibility. One issue is that there is still much to be learned about the localization and function of the different members of the NRG gene family in the local

circuits. Further so far only one study has looked at the impact of NRG1–ErbB4 signaling in VIP+ interneurons on cortical plasticity11. The manipulations that we propose should serve as a

starting point for intervention. Better alternatives could very well arise as new discoveries are made that deepen our understanding of the NRG family in local circuits. Another concern is

the absence of clinical trial data on the feasibility of stereotactic injection into brain of patients with Sz or other type of psychiatric illness. While a number of clinical studies have

been carried out or are underway for a variety of neurological disorders119, use of these approaches for psychiatric disorders could potentially be thwarted by a number of obstacles due to

the unique nature of these illnesses. For example, symptoms like paranoia and command auditory hallucinations are common in these disorders. Whether this patient population would be amenable

to intracerebral surgical injection is unknown. Other issues that would need to be resolved relate to treatment duration and dosing given the chronic and heterogeneous nature of psychiatric

illnesses. Phase I and II clinical trial data indicate cargo expression from intracerebrally injected recombinant AAV can persist for at least 2 years57,58. Although development of this

therapeutic modality is still emerging, evidence from preclinical studies suggests both longer term expression and inducible expression are possible. For example, studies in primates show

that expression from intracerebrally injected virus is maintained for up to 15 years without cytotoxicity or Lewy body formation68. Likewise, progress has been made on incorporating

inducible genetic elements into AAV vectors, which would enable tighter control of cargo expression levels120. In summary, despite over 50 years of research and development, the drugs

available to treat Sz largely fail to remedy the cognitive and executive function deficits. Although there are still a number of open questions regarding feasibility as discussed above, gene

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in mice. _Schizophr. Bull._ 44, 865–875 (2018). PubMed  Google Scholar  Download references AUTHOR INFORMATION Author notes * Liang Shi Present address: Department of Cell Biology, Emory

University School of Medicine, Atlanta, GA, USA AUTHORS AND AFFILIATIONS * Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, 1460 Laney Walker

Boulevard, Augusta, GA, 30912, USA Liang Shi & Clare M. Bergson Authors * Liang Shi View author publications You can also search for this author inPubMed Google Scholar * Clare M.

Bergson View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Clare M. Bergson. ETHICS DECLARATIONS CONFLICT OF INTEREST

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THIS ARTICLE CITE THIS ARTICLE Shi, L., Bergson, C.M. Neuregulin 1: an intriguing therapeutic target for neurodevelopmental disorders. _Transl Psychiatry_ 10, 190 (2020).

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