1. Introduction
Neuregulin 1 (NRG1) /ErbB4 signaling is one of the essential pathways to developing the central and peripheral nervous system. The role of this pathway to regulate neuronal migration, myelination, differentiation, cortical lamination, and synaptic plasticity has been reported in several studies (Mei & Xiong, 2008; Nave & Salzer, 2006). This pathway is required for brain development not in the fetal period but in adulthood and its discrepancies are involved in the pathogenesis of some neurodevelopmental disorders (Mei & Xiong, 2008). 
In addition, some polymorphisms of NRG1 have contributed to temporal lobe epilepsy and epileptogenesis (Tan et al., 2012; Zhu et al., 2016). It is well understood that a deficit in the NRG1/ErbB4 pathway has been associated with schizophrenia in the human population and animal models (Mei & Xiong, 2008; Moa & Chen, 2017). In addition, some polymorphism of NRG1 has contributed to temporal lobe epilepsy and epileptogenesis (Tan et al., 2012; Zhu et al., 2016). 
Absence seizures appear during childhood with different clinical manifestations (Jafarian, et al. 2013). Spontaneous and synchronous spike-wave discharges (SWDs) are the main characteristics of the electroencephalogram for the absence epilepsy. WAG/Rij rats have been considered the most valid genetic model of absence epilepsy. Absence seizures appear in adult WAG/Rij rats, mostly after three months of age (Karimzadeh et al., 2017). To clarify the developmental alteration of the NRG1/ ErbB4 signaling pathway and TRPV1 receptor, two stages of development were assessed. Two- and six-month-old of age have been considered as the early- and late-stage of development.
In addition, imbalances between excitatory and inhibitory receptors have a critical role in developing absence epilepsy (Zifkin, et al., 2005). NRG1 and its receptor ErbB4 regulated excitatory-inhibitory neurotransmission and sensorimotor gating (Agarwal et al., 2014). NRG1/ERbB4 pathway modulated GABAergic and dopaminergic transmission as well as glutamate in the synapses (Agarwal et al., 2014; Marenco et al., 2011). Overexpression of NRG1 disrupted excitatory-inhibitory connections and reduced synaptic plasticity (Barros et al., 2009; Penzes, et al., 2011). NRG1/ERbB4 signaling modulated neural excitability as well as long-term potentiation (Pitcher, et al., 2008). Careful regulation of the NRG1/ErbB4 pathway preserved a critical balance between excitation and inhibition in the nervous system. ErbB4 regulated the activity of hippocampal and cortical pyramidal neurons (Buonanno, 2010; Mei & Xiong, 2008), while dysfunction of them perturbed neuronal network activity (Fisahn, et al, 2009; Nason, et al., 2011), functional connectivity, and synaptic plasticity (Stefan, 2008). 
Transient receptor potential vanilloid 1 (TRPV1) with permeability to Ca+2 ions modulated neurotransmitter release and synaptic transmission (Saffarzadeh et al., 2016). Involvement of TRPV1 in the pathogenesis of some disorders, such as schizophrenia, hyperalgesia, and different kinds of epilepsy, including temporal lobe and tonic-clonic seizures has been indicated (Chahl, 2007; Chizh et al., 2007; Shamsizadeh, et al., 2016; Sun et al., 2013).
The regulatory effect of the NRG1/ERbB4 pathway on the TRPV1 function has been shown in the sensory neurons (Canetta, Luca, Pertot, Role, & Talmage, 2011). The lack of NRG1 level was accompanied by TRPV1 deficit (Mei & Nave, 2014). This regulatory effect derived us to evaluate the correlation between NRG1/ERbB4 and TRPV1 expression during the rat’s life span. According to the role of these pathways in neuronal development and excitability regulation, this study evaluated alternation in NRG1/ERbB4 and TRPV1 expression during absence seizures development in the WAG/Rij rats.

2. Materials and Methods 
Animals
Male WAG/Rij and Wistar rats were maintained in the animal lab with free access to food and water and 12 h light and dark cycle for one week and divided into four groups of two- and six-months of age (n=6 in each group). The protocol of animal ethics was approved by Shefa Neuroscience Research Center.

Detecting epileptic rats
Two silver electrodes were implanted in the parietal cortex and the reference electrode was inserted into the nasal bone. Electrocortocencephalogram )ECoG( was recorded for six hours under sedated state induced by intraperitoneally (i.p.) injection of fentanyl (3 μg/kg), which was repeated every 20-30 min (Karimzadeh et al., 2016). Signals were amplified (EXT-02 F; NPI, Germany) and stored in a digital oscilloscope. Signals were analyzed by AxoScope 10 software. Six-month-old WAG/Rij rats were included in the study because of SWDs appearance in their ECoG (Karimzadeh et al., 2013). Two-month-old WAG/Rij rats as well as two- and six-month-old Wistar rats without any SWDs appearance in their ECoG were considered non-epileptic rats (Jafarian et al., 2015). 

Western blot analysis 
Tissues of the somatosensory cortex and hippocampus were manually dissected and homogenized in lysis buffer containing Tris-HCl (20 mM), EDTA (1 mM), Triton 100X (1 %), and 1 mM of phenylmethylsulfonylfluoride, aprotinin, pepstatin, as well as leupeptin (1 µg/ml). The clear supernatant was gathered and the protein concentrations were measured by Bradford’s test. 
The same protein concentrations were loaded in 12% SDS-polyacrylamide gel electrophoresis and separated by electro-blotted onto polyvinylidene difluoride (PVDF) membranes. Following blocking, the PVDF membranes were incubated for 3 hours at room temperature with primary antibodies against ErbB4, NRG1, TRPV1, and β actin (1:500, Santa Cruz). PVDF was washed and incubated with a secondary antibody (HRP- conjugated goat anti-mouse; 1:1000; Santa Cruz). Immunoreactivity was visible by ECL kit and exposed to X-ray film. The developed films were scanned by a Bio-Rad scanner. The images were analyzed by the monomeric bands’ data with Image J software.

Statistical analysis
All data are given as Mean±S.E.M and were analyzed by one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test. The probability values less than 0.05 were considered significant. The PASW Statistics 20 was used for statistical analysis.

3. Results
ECoG was monitored for 6 hours in all rats. Six-month-old WAG/Rij rats indicated SWDs in their ECoG were considered epileptic rats. The mean of SWDs frequency and amplitude was 5-10 Hz and 0.5-1.5 mV, respectively. Two-month-old rats (Wistar and WAG/Rij) as well as six-month-old Wistar rats with no SWDs in their ECoG had criteria to be included in the non-epileptic groups (Figure 1). 

Cortical protein level 
The total protein levels of NRG1, ErbB4, and TRPV1 were measured by immunoblotting in the somatosensory cortex (Figure 2A). The protein levels of NRG1 were significantly lower in the two- and six-month-old WAG/Rij rats compared to the six-month-old Wistar rats (P<0.001, Figure 2B). Furthermore, the NRG1 levels of the six-month-old Wistar rats were significantly higher compared to two-month-old Wistar rats (P<0.001, Figure 2B). The levels of NRG1 had no significant difference in two-month-old WAG/Rij rats compared to age-matched Wistar rats.There was no significant difference in the NRG1 levels between two- and six-month-old WAG/Rij rats.
The protein levels of ErbB4 were significantly lower in the two- and six-month-old WAG/Rij rats compared to six-month-old Wistar rats (P<0.01, Figure 2B). Further, it showed a significantly lower expression in the six-month-old WAG/Rij rats compared to two-month-old WAG/Rij rats (P<0.01, Figure 2B). The ErbB4 levels did not significantly differ between two-month-old Wistar and WAG/Rij rats. The levels of TRPV1 in two- and six-month-old WAG/Rij rats were significantly lower than age-matched Wistar rats (P<0.01, Figure 2B). TRPV1 highly expressed in 6-month-old Wistar rats compared to two-month-old Wistar rats (P<0.05, Figure 2B).

Hippocampal protein levels
The total protein levels of NRG1, ErbB4, and TRPV1 were measured by immunoblotting in the hippocampus (Figure 3A). The protein levels of NRG1 were significantly lower in the six-month-old WAG/Rij rats compared to two-month-old Wistar and WAG/Rij rats (P<0.01 and P<0.05, respectively). There was no significant difference in six-month-old WAG/Rij rats compared to age-matched- Wistar rats (Figure 3A).
The protein levels of ErbB4 were significantly lower in the two-month-old WAG/Rij rats compared to age-matched Wistar rats (P<0.01, Figure 3B). The ErbB4 levels were significantly higher in six-month-old WAG/Rij rats compared to six-month-old Wistar rats (P<0.001, Figure 3B). In addition, the ErbB4 levels were significantly lower in the six-month-old Wistar rats compared to two-month-old Wistar rats (P<0.01, Figure 3B).
The levels of TRPV1 were lower in two-month-old WAG/Rij and six-month-old Wistar rats compared to two-month-old Wistar rats (P<0.001 and P<0.01, respectively, Figure 3B). TRPV1 highly expressed in six-month-old WAG/Rij rats compared to age-matched Wistar rats as well as two-month-old WAG/Rij rats (P<0.01, Figure 3B).

Correlation between expression of NRG1/ERbB4 and TRPV1
The correlation between protein expression of NRG1/ERbB4 and TRPV1 independently to rats’ strain was analyzed in the somatosensory cortex and hippocampus (Figure 4). Cortical correlation between protein levels of NRG1 and TRPV1 showed that high expression of NRG1 (Figure 4A; r=0.6), as well as ERbB4 (Figure 4B; r=0.8), was accompanied by a high level of TRPV1.
Hippocampal correlation between gene and protein levels of NRG1/ERbB4 and TRPV1 showed high protein level of ERbB4 was accompanied by an increase in the TRPV1 protein expression (Figure 4D; r=0.9). There was no significant correlation between NRG1 and TRPV1 expression (Figure 4C; r=0.04). 

4. Discussion
Cortical expression
Our findings showed the lack of NRG1/ERbB4 as well as TRPV1 expression in the somatosensory cortex of both juvenile and adult WAG/Rij rats compared to Wistar rats. The critical role of the NRG1/ ErBb4 signaling pathway and TRPV1 receptor in the development of the brain and cortical lamination has been shown (Rico & Marín, 2011; Storozhuk, et al., 2019). During the development of the brain, NRG1 through the activation of ErbB2 and ErbB4 helped radial glia survival and normal neuronal migration in the cerebellum and cerebral cortex (Anton, Marchionni, Lee, & Rakic, 1997). Further, the important role of TRPV1 receptors in the formation of healthy neuro-glial communication is impressive (Ramírez-Barrantes et al., 2016). TRPV1 promoted astrocyte migration in the inflammatory condition and its deficits reduced GFAP (as a specific marker for astrocytes) expression in the cortical and subcortical areas (Wang et al., 2019; Yang et al., 2019). 
Multiple studies have insisted on the importance of astrocytes rather than neurons in the pathogenesis of several neurological disorders, including epilepsy (Kim, Park, & Choi, 2019; Sidoryk-Wegrzynowicz, et al., 2011). In addition, we showed the lack of GFAP expression in the different cortical layers in the WAG/Rij rats (Karimzadeh et al., 2017). 
It seems that disturbances in the cortical expression of NRG1/ERbB4 as well as TRPV1, especially in the early stage of development might be involved in the cortical astrocyte attenuation, which has a critical role in absence seizure pathogenesis.
In addition, NRG1 is required for the balance of excitatory and inhibitory neurotransmission in the cortex (Agarwal et al., 2014). NRG1 regulated cellular properties associated with GABAergic interneurons and increased excitatory synaptic transmission of GABAergic interneurons in the hippocampal neurons (Longart, et al., 2004; Yau, Wang, Lai, & Liu, 2003). NRG1 was also capable to induce the GABAa receptors in the cerebellar granular cell culture (Ozaki, Kishigami, & Yano, 1998; Rieff et al., 1999).
The erbB4 receptor is the main signaling partner of the NRG1 signaling pathway (Birchmeier, 2009). The over-expression of the ErbB4 receptor has been shown in the cortical inhibitory interneurons of humans and primates (Neddens & Buonanno, 2011; Rieff et al., 1999; Vullhorst et al., 2009). Cortical mRNAs of ErbB4 are expressed by dispersed GABAergic neurons (Lai & Lemke, 1991; Woo et al., 2007). 
Further, it has been reported TRPV1 modulated GABAergic synapses (Chávez, et al., 2014). It has been suggested that TRPV1 could regulate excitatory afferents to GABAergic interneurons (Ferrini, et al., 2007; Liao, et al., 2011).
It seems that cortical decrease of NRG1/ ErbB4 signaling and TRPV1 activity in the epileptic WAG/Rij rats led to a deficit in the inhibitory inputs of pyramidal cells and a decrease in GABA release from cortical interneurons. Deficits in cortical inhibitory transmission and synapses probably trigger SWDs firings in the epileptic WAG/Rij rats.

Hippocampal expression
We showed high expression of hippocampal NRG1 / ErBb4 and TRPV1 at the early stage of Wistar rats’ lifespan (two months of age) but not in WAG/Rij rats. The role of NRG1 in synaptic differentiation, such as dendritic spine size, modulation of long-term potentiation (LTP), and enhancement of entorhinal-hippocampal synaptic transmission has been reported (Kwon, et al., 2005; Li, et al., 2007; Li et al., 2014; Roysommuti, Carroll, & Wyss, 2003; Shamir et al., 2012). 
NRG1 improved cognitive impairment induced by isoflurane in aged mice (Li et al., 2014). NRG1/ ErbB4 activation compensated for the impairment of LTP induced by Aβ1-42 in the hippocampal slices (Min et al., 2011).In addition, TRPV1 has a crucial role in the regulation of hippocampal synaptic transmission (Hurtado-Zavala et al., 2017). TRPV1 receptors were highly expressed in the molecular layer of the hippocampus. These cells could process inputs/outputs in the hippocampal layers (Anstötz, Lee, & Maccaferri, 2018).
Behavior, emotional, and cognitive deficits have been indicated in children who suffer from absence epilepsy and epileptic WAG/Rij rats (Caplan et al., 2008; Jafarian et al., 2015; Masur et al., 2013). It seems that deficits of NRG1/ERbB4 as well as TRPV1 expression in the early stage of the life span of WAG/Rij rats disrupted the development of the hippocampus and might impair memory and cognition in the adult WAG/Rij rats. In addition, hippocampal TRPV1 expression increased in adult (epileptic) WAG/Rij rats but not in adult Wistar rats. TRPV1 receptor increased seizure susceptibility in the chemical induction of seizures (Kong et al., 2014). Hippocampal expression of TRPV1 increased in the patients and animal models with mesial temporal lobe epilepsy (Gonzalez-Reyes, Ladas, Chiang, & Durand, 2013; Sun et al., 2013).
Hippocampal glutamate release is enhanced following endogenous cannabinoid administration (Gonzalez-Reyes et al., 2013). Activation of TRPV1 increased toxicity and cell death in dorsal root ganglions and neocortex (Olah et al., 2001; Shirakawa et al., 2008). Furthermore, we showed that ERbB4 expression increased in adult epileptic WAG/Rij rats. 
Down-regulation of ErbB4 in the hippocampal interneurons improved learning and memory in the animals with genetically manipulated ErbB4 receptors (Tian et al., 2017). Enhancement of LTP in the genetically hippocampal ErbB4 deficient has been indicated (Pitcher et al., 2008). In addition, ErbB4 is selectively expressed in the hippocampal interneurons and has a regulatory effect on glutamatergic synapses in the inhibitory interneurons (Vullhorst et al., 2009). These observations showed the reciprocal role of the ERbB4 receptor in neuronal excitability as well as memory encoding in the hippocampus. It seems that a decrease in ERbB4 expression is required for adult hippocampal function. High levels of hippocampal ERbB4, as well as TRPV1 receptor in the adult WAG/Rij rats, probably developed absence seizures in the WAG/Rij rats. 

Signaling correlation between NRG1/ERbB4 and TRPV1
We showed a significant correlation between NRG1 or ERbB4 and TRPV1 expression levels in the neocortex and hippocampus. The expression of NRG1 or ERbB4 and TRPV1 follows a similar pattern during the life span of Wistar and WAG/Rij rats. An increase in NRG1 or ERbB4 expression is accompanied by high levels of TRPV1 in Wistar rats. A deficit in the NRG1 or ERbB4 expression is accompanied by a diminution of TRPV1 in WAG/Rij rats.
It is well understood that the interaction between NRG1 and ERbB receptors can facilitate cell-cell communication during the development of the brain to form healthy functional synapses (Bao, et al., 2003; Leimeroth et al., 2002).
Activation of the tyrosine kinase domain of the ERbB4 receptor leads to phosphorylation of the intracellular domain and results in the main signaling cascades downstream of NRG1/ERbB4 pathway. The mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways are the main downstream cascades of this signaling (Liu, et al., 2007). 
NRG1 modulated the functional TRPV1 in the sensory neurons (Bao et al., 2004). Back signaling of ERbB4 enhanced TRPV1 receptors through the activation of phosphatidylinositol-3-kinase (Bao et al., 2004; Canetta et al., 2011).
It has been suggested that the activation of PI3K by NRG1 back-signaling up-regulated TRPV1 receptors. The intracellular domain of NRG1 is required to activate PI3K and affect the TRPV1 regulation (Canetta et al., 2011). Furthermore, activation of MAPK in the injured neurons of dorsal root ganglions hyper synthesized TRPV1 receptors (Chen et al., 2016). In addition, the role of TRPV1 receptors in epileptogenesis has been reported. Cortical as well as hippocampal TRPV1 receptors are highly expressed in epileptic people suffering from temporal lobe epilepsy (Sun et al., 2013). Functional discrepancies of TRPV1 receptors altered the seizure susceptibility in the animal model of tonic-clonic epilepsy (Jia et al., 2015). In contrast, epileptogenesis was postponed by the administration of TRPV1 agonist in the kainic acid model of epilepsy (Lee et al., 2011). According to our findings, alteration in NRG1/ ERbB4 signaling pathway disturbed TRPV1 expression and possibly triggered SWDs appearance during the development of WAG/Rij rats. 

5. Conclusion 
It seems that the disturbance in the expression of Neuregulin 1 protein has a notable effect on the down-regulation of ERBB4 and TRPV1 receptors. It might also be concluded that the reduction of the mentioned receptors would play an important role in the pathophysiology of absence epilepsy.

Ethical Considerations
Compliance with ethical guidelines
All experiments were performed according to the protocol approved by the ethical principles of working with laboratory animals of Iran University of Medical Sciences (IR.IUMS.REC.1396.023). 

Funding
The Iran University of Medical Sciences supported this work (Grant No.: 96-01-117-30641).

Authors' contributions
Conception and design of research: Fariba Karimzadeh; Administrative, technical, and material support: Farideh Talebi, Samira Ghorbani; Perform of experiment and Acquisition of data: Leila Alizadeh, Farideh Talebi; Analysis and interpretation of data: Fatemeh Akhlaghi; Manuscript: Sedigheh Sadat Moeeni; Critical revision of the manuscript for important intellectual content: Fariba Karimzadeh.

Conflict of interest
The authors declare no conflict of interest.

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