Neurological Disorders in Animals with NKA Mutations: History
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Contributor:
Alisa A. Markina
,
Rogneda B. Kazanskaya
,
Julia A. Timoshina
,
Vladislav A. Zavialov
,
Denis A. Abaimov
,
Anna B. Volnova
,
Tatiana N. Fedorova
,
Raul R. Gainetdinov
,
Alexander V. Lopachev

Endogenous cardiotonic steroids are involved in the pathogenesis of affective disorders, including depression and bipolar disorder, which are linked to dopaminergic system dysfunction. Animal models have shown that the cardiotonic steroid ouabain induces mania-like behavior through dopamine-dependent intracellular signaling pathways. In addition, mutations in the alpha subunit of Na+,K+-ATPase lead to the development of neurological pathologies. Evidence from animal models confirms the neurological consequences of mutations in the Na+,K+-ATPase alpha subunit. 

  • Na+,K+-ATPase
  • cardiotonic steroids
  • dopamine
  • bipolar disorder

1. Introduction

It is known that both neurons and glial cells need to constantly restore their resting membrane potentials. Maintenance and restoration of the resting potential is facilitated by Na+,K+-ATPase (NKA), a cytoplasmic membrane protein complex that exports three Na+ ions out of the cell in exchange for two K+ ions. This pump action is facilitated by the α subunit, part of a membrane protein complex that also includes the β and γ subunits [1]. In neurons, aside from the ubiquitous α1 isoform, a neuron-specific isoform is present—the α3, while glial cells express the α2 isoform in addition to α1 [2]. Na+ export is necessary for neurons to restore the resting potential after the propagation of an action potential, and it facilitates Na+-conjugated transport processes [3]. Glial cells use the Na+ and K+ gradient to transport various compounds across the membrane, including excess neurotransmitters from the synaptic cleft and energy-intensive substrates transported into neurons [4].
A large body of evidence hints at the association of NKA dysfunction with the development of neurodegenerative and neuropsychiatric diseases. For example, mutations in the ATP1A3 gene cause rapid-onset dystonia parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) [5]. Neurotoxic α-synuclein aggregates, which are a hallmark of Parkinson’s disease, bind to the neuronal α3-subunit of NKA, disrupting its function [6]. Oxidative stress (OS), which can be caused by toxic dopamine metabolites [7], as well as protein kinase C (PKC) activation [8] also cause dysfunction of neuronal NKA. Thus, there is reason to further study the role of NKA dysfunction in pathophysiological processes in the central nervous system (CNS).
In addition to its role in maintaining resting membrane potential, NKA is also involved in a number of intracellular signaling pathways and is a receptor for cardiotonic steroids (CTS), which can induce changes in intracellular signaling when binding to the enzyme. To date, thanks to the use of mass spectrometric analysis, enough data have been accumulated that allow us to consider CTS as endogenous hormone-like compounds in mammals, including humans. Endogenous ouabain was identified in human blood plasma [8][9], and its role in the development of various diseases, including arterial hypertension, was shown [8][9][10]. The presence of marinobufagenin in human blood was identified [11]. Additionally, endogenous CTS were isolated from the bovine adrenal glands [12]. From the bovine hypothalamus, a compound with an integer mass measured by HPLC-mass spectrometry equal to ouabain was isolated by affinity chromatography [13]. Thus, it is assumed that endogenous ouabain can be produced in the brain and adrenal glands of mammals. It has been shown that its amount can increase in response to an increase in tissue NaCl concentration. Increased content of endogenous ouabain in the brain is associated with epilepsy and motor neuron dysfunction [14]. However, there is currently no complete understanding of the physiological role of CTS in the CNS. There is also virtually no knowledge about the pathways of their biosynthesis in the brain and their regulation.
In addition to endogenous CTS, the CNS can also be affected by exogenous factors: the use of the CTS digoxin to treat patients with heart failure can lead to a wide range of neuropsychiatric side effects, such as fatigue, depression, psychosis, and delirium [14][15]. In various experimental models, it was shown that CTS can affect the efficiency of Na+ and K+-dependent processes by inhibiting NKA [16]. Thus, inhibition of the α3 subunit in neurons leads to the inability to quickly restore the Na+ gradient and enable action potential generation [17]. It is also known that ouabain causes increased release of GABA and decreased rate of GABA reuptake [18]. In addition, the NKA in the CNS has a number of functions specific to each isoform that are not directly related to pump activity, including the regulation of other membrane proteins and the activity of intracellular signaling cascades [8]. Via binding to NKA, CTS can influence the work of membrane and cytoplasmic proteins with which they interact [19][20][21]. Experimental data obtained in an amphetamine-induced model of mania in mice indicated the possible involvement of endogenous CTS in the development of bipolar disorder [22]. When entering the bloodstream, endogenous CTS affect the excretory and cardiovascular systems [14]. However, there is currently no complete picture of the involvement of CTS in physiological and pathophysiological processes in the CNS.

2. Neurological Disorders in Animals with NKA Mutations

The α3 subunit of NKA is encoded by the ATP1A3 gene. To date, four mouse models used to study the in vivo consequences of mutations in the ATP1A3 gene have been described. The creation of model animals—mice in which the α3 subunit gene promoter (Atp1a3) is used to control the expression of the fluorescent protein ZsGreen1 (a3NKA-ZsGreen1 mouse model) [23]—made it possible to determine the localization of the α3 subunit in brain tissue. It was shown that the signal intensity was highest in the neuronal bodies located in the stem structures, including the substantia nigra, some nuclei of the thalamus and cerebellum. No fluorescence was detected in astrocytes and brain white matter.
Mutations in the ATP1A3 gene have an autosomal dominant inheritance pattern. Homozygous mutants die shortly after birth. Therefore, viable and fertile heterozygotes are used to study all four in vivo models. These models display symptoms and endophenotypes similar to those seen in the manic and depressive phases of bipolar disorder, rapid-onset dystonia parkinsonism, epilepsy, alternating hemiplegia of childhood, and CAPOS syndrome to varying degrees (Table 1) [3].
Table 1. ATP1A3 genetically modified models.
Model Symptoms of Affective Disorders Symptoms of Neurological Disorders In Vivo Electrophysiology Data Changes in Dopamine Levels References
1.1
Myk/+–		 Mania:
Hyperactivity
Sleep disturbances
Dysregulated circadian rhythm
Tendency to engage in high-risk behavior
Increased sensitivity to amphetamine
Decreased anxiety
High impulsivity
Lower spatial memory		 Tremor
Impaired gait		 - - [24][25][26]
1.2
Mashl+/−		 Mania:
Hyperactivity
Increased excitability
Decreased anxiety
High impulsivity
Lower spatial memory		 Tremor
Impaired gait		 High excitability,
prolonged arousal after a threshold stimulus		 - [27]
1.3
NKA1A3tm1Ling		 Mania:
Hyperactivity
Increased sensitivity to amphetamine
Decreased anxiety
Impulsivity
Low habituation
Depression:
Anhedonia
Despair-like behavior
Increased anxiety
Impaired learning and memory
Decreased socialization		 - - Mania:
Not different from wild type
Depression:
Negative correlation with vertical activity		 [25][28][29]
1.4
Atp1a3tm2Kwk/+		 Mania:
Hyperactivity
Impulsivity
Lower spatial memory		 Impaired gait
Symptoms similar to RDP		 - - [30]
[31]
Heterozygous Myshkin mutants (NKA13AMyk/+; Myk/+) (1.1 in Table 1) carry a missense mutation with an amino acid substitution at position 810 (I810 N). Such NKA α3 subunits are expressed normally but are not functionally active. Myshkin mutants were originally developed as a preclinical model of epilepsy because heterozygotes exhibited spontaneous seizures [24]. By crossing with seizure-resistant C57BL/6NCr mice, mutants that did not exhibit seizures were obtained [32]. So far, Myk/+ mutants have been shown to be valid models of mania [33]. In behavioral tests, Myk/+ mutants demonstrated hyperactivity, circadian rhythm and sleep disturbances [34], risk-taking tendencies, and increased sensitivity to D-amphetamine [25][35]—these symptoms are seen in patients in the manic stage of bipolar disorder. Additionally, administration of lithium and valproic acid, effective in mania therapy, has been shown to normalize behavior in heterozygous mice. However, it is not known at this time whether an endophenotype of depression is possible in this model in response to stressors. Myk/+ mice were also shown to exhibit a number of disturbances in circadian behavioral rhythms related to the processing of sensory visual information but without disturbances in the function of clock genes [36]. The authors suggested a link between the identified circadian rhythm abnormalities in this mouse model and the sleep disorders observed in parkinsonism. Some reviews on rush-induced dystonia-parkinsonism suggested the use of Myshkin heterozygotes as models of this disease [37]. The 4-week-old Myk/+ displays a different gait than the wild type, unstable with a shorter stride and accompanied by tremor. Tremor and gait problems are symptoms characteristic of parkinsonism. Changes in glucose metabolism and functional brain connectivity have also been shown in mice of this line. However, Myk/+ heterozygotes are not adequate models of RDP and parkinsonism; their endophenotype is more similar to that of alternating hemiplegia of childhood [26].
Heterozygous mutants of Mashlool (α+/D801N; Mashl+/−) (1.2 In Table 1) also carry a missense mutation with an amino acid substitution at position 810. A similar amino acid substitution at the same position is found in AHC patients [38]. Hyperactivity, reduced learning ability, memory problems, tremor, and shorter stride length have been shown for this line of mice compared to wild-type mice. Dystonia, hemiplegia, and hyperexcitability were found in Mashl+/−. In vivo electrophysiology data show that heterozygotes require fewer electrical stimulations for full excitation than wild-type animals; in addition, registration of electrical activity of the amygdala and hippocampus shows that the duration of full excitation of these structures after stimulation is significantly longer in heterozygotes than in wild-type mice. Mashl+/− mutants show spontaneous seizures and have an increased mortality [27]. Mashlool mutant data show that this lineage can serve as an AHC model with some reservations, but it is difficult to judge whether it can be an adequate model for studying bipolar disorder.
Heterozygous mutants with a point mutation in the fourth intron (NKA1A3tm1Ling, NKA1A3+/−, α+/KOI4) (1.3 in Table 1) show an approximately 60% reduction in α3-subunit expression in the hippocampus [28] because of aberrant splicing. At the same time, total NKA activity is reduced by 15% compared to the wild type. Behavioral features of intact (unstressed) heterozygotes are hyperactivity, decreased anxiety, and sensitivity to methamphetamine. No behavioral manifestations of neurological disorders were found in intact heterozygotes [29]. High-performance liquid chromatography showed no change in the levels of serotonin, dopamine, and their metabolites in the striatum in heterozygotes compared to wild-type animals. However, heterozygotes showed increased locomotor activity when presented with methamphetamine, which may be related to disturbances in the dopaminergic system [28]. α+/KOI4 mice exposed to chronic variable stress (CVS) exhibit behaviors similar to those observed in the depressive phase of bipolar disorder: anhedonia, despair-like behavior, weight changes, increased anxiety, and impaired memory and socialization. At the same time, NKA1A3 activity was reduced by 33% compared to the stressed wild type, consistent with the endophenotype of depression [26]. Thus, CVS-treated α+/KOI4 mutants can serve as a model for the depressive phase of bipolar disorder. In males with this mutation, however, no overt symptoms of parkinsonism or dystonia were found before or after stressors. However, for females, chronic stress was shown to induce coordination problems. In addition, rearing in stressed heterozygotes of both sexes was shown to have a negative correlation with levels of dopamine and its metabolites, which was not observed in wild-type mice [29].
Heterozygous Atp1a3tm2Kwk/+ mutants (1.4 in Table 1) have directional deletion of exons 2–6. Hyperactivity in both cell and open field tests was shown for them, but their anxiety level is not significantly different from that of wild-type animals. Heterozygotes have a higher level of coordination and motor balance compared to the wild type. Stressors do not cause dystonia-like symptoms, but microinjections of kainate into the cerebellar vermis induced a similar state. Electrophysiological studies on slides showed a connection of the mutation to the GABAergic system but not to the dopaminergic system [30]. Heterozygotes at 4 weeks of age show a shorter stride length compared to the wild type. Older heterozygotes (6–12 weeks old) do not show gait abnormality in the absence of stressors. However, when exposed to stressors, they begin to take shorter steps when moving, compared to controls. This is very similar to the manifestation of RDP, the symptoms of which in humans can be triggered by stress. It has been suggested that Atp1a3tm2Kwk/+ mutants may be a good model for RDP, although researchers have not reported dystonia or other symptoms of parkinsonism (postural instability, bradykinesia) [31].
For all four genetic models, increased impulsivity, a propensity for risk-taking behavior, and decreased habituation have been shown to varying degrees. All of these behavioral traits are symptoms of mania. The most striking symptoms of a mania-like state are noted in Myshkin mutants. However, there is currently insufficient information about dopamine levels in this line of mice. The depressive phase of bipolar disorder is best reproduced in CVS-exposed NKA1A3tm1Ling mutants. A correlation was found between the activity of stressed mice of this lineage and dopamine levels, but the relationship between dopamine levels and the mania-like state of unstressed heterozygotes carrying this mutation is not well understood.
Gait impairment is one of the symptoms of parkinsonism, including RDP. Gait abnormalities in mice were shown for three of the four models. The Atp1a3tm2Kwk/+ model is the closest to RDP, but it does not demonstrate the full range of classic parkinsonism symptoms. Thus, no genetic model associated with a mutation in the ATP1A3 gene can be called sufficiently reliable to study parkinsonism, at least for the time being. Nevertheless, the manifestation of both manic behavior and motor disorders simultaneously in the models may indicate that mutations in the α3-subunit of NKA can phenotypically manifest these two pathologies. Further research is needed to understand the mechanisms of the relationship between these pathologies.
Mutations that disrupt the α2-subunit of NKA, which is expressed in the brain in glial cells, can also lead to the development of various neurological and neuropsychiatric disorders. Variants in the ATP1A2 gene, which encodes the α2-subunit of NKA, are associated with familial hemiplegic migraine. For example, patients with the G301R mutation are affected by a complex syndrome characterized by migraine comorbidity with epilepsy, motor symptoms, and depression or obsessive–compulsive disorder [39][40]. This mutation was successfully replicated in mice, which displayed impaired glutamate uptake and altered inflammatory cytokine signaling [39][40].

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11071820

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