Tau is a microtubule-associated protein encoded in humans by the microtubule-associated protein tau gene, MAPT, on chromosome 17 (Wang and Mandelkow, 2016). In the brain, tau is most abundant in neurons, including neuronal axons, somatodendritic compartments, and nuclei, but it is also present in glia and, to a lesser degree, extracellularly (Morris et al., 2011; Wang and Mandelkow, 2016). The functions of tau in the brain are multifaceted, but its most well-characterized role is in microtubule binding and assembly. Tau is natively unfolded and highly soluble, thus exhibiting little tendency for aggregation. However, under pathological conditions, the hyperphosphorylation of tau reduces its affinity for tubulin and is thought to drive abnormal aggregations of phosphorylated tau (p-tau), such as neuropil threads or neurofibrillary tangles (NFTs), resulting in tauopathies (Wang and Mandelkow, 2016; Kovacs, 2017).

Endogenous tau is also implicated in neuronal activity (Wang and Mandelkow, 2016), though this role of tau is less well understood. Neuronal excitation, in turn, also regulates tau by promoting extracellular release and phosphorylation. Rapid and persisting increases in extracellular tau following in vivo (Yamada et al., 2014) or in vitro (Pooler et al., 2013) neuronal stimulation suggest that tau amplification is associated with pathological neuronal activation. Given that seizure and chronic epilepsy animal models result in prolonged tau phosphorylation (Liang et al., 2009; Liu et al., 2016; Alves et al., 2019), a growing body of research is examining the role of pathological tau in epilepsy and mechanisms underlying epilepsy and tauopathy comorbidities.

In Alzheimer’s disease (AD), which is the most common tauopathy, an estimated 60% of patients have seizures and subclinical epileptic activity (Vossel et al., 2016, 2017; Lam et al., 2020; Horvath et al., 2021). Seizures are more common in AD and dementia with Lewy bodies than in primary tauopathies, such as frontotemporal dementia and progressive supranuclear palsy (Beagle et al., 2017). However, the possibility of seizures and hyperexcitability in primary tauopathies should not be ruled out, as they occur more frequently in these diseases than in the general population (Beagle et al., 2017; Sanchez et al., 2018). Myoclonus, a sign of network hyperexcitability, is observed in a subset of patients with corticobasal degeneration (Armstrong et al., 2013), and epileptic activity is present in the FTDP-17 animal model of frontotemporal dementia with parkinsonism (Garcia-Cabrero et al., 2013).

Furthermore, tau pathology is repeatedly found in human epilepsy (Sanchez et al., 2018). In a post-mortem series of 138 refractory epilepsy cases of diverse causes, Braak staging of NFTs in the age group 40–65 years revealed increased Braak stages III/IV compared with data from an age-matched series of non-epilepsy cases (Thom et al., 2011). Abnormally high total tau and p-tau levels were also detected in cerebrospinal fluid of status epilepticus patients, with increased total tau correlating with greater risk of developing chronic epilepsy (Monti et al., 2015). Given that neurodegenerative conditions characterized by hyperphosphorylated tau aggregations exhibit increased rates of epilepsy, epilepsies are being re-conceptualized within a tauopathy context (Xi et al., 2011; Sanchez et al., 2018; Ali et al., 2019).

As such, the present review seeks to explore the following three main questions: (1) Does tau play a role in mediating network hyperexcitability and seizure activity across different epilepsy disorders? (2) Do comorbid tauopathies and epilepsies stem from independent or common mechanisms? (3) How do tauopathy and epilepsy comorbidities contribute to disease-related cognitive impairment? In light of evidence indicating tau-mediated epileptic activity and dysregulation of tau-related cell signaling pathways across seizure disorders, we propose a potential overarching mechanism (Figure 1) whereby endogenous tau helps enable network hyperexcitability, which triggers homeostatic responses aimed, in part, to disable tau activity by phosphorylation. Resulting tau hyperphosphorylation and aggregation may in turn further contribute to cognitive impairments seen in some seizure disorders.

Across various animal models that exhibit epilepsy, reducing tau levels reduces network hyperexcitability, seizure severity, and latency to seizure stages (Roberson et al., 2007; Ittner et al., 2010; DeVos et al., 2013; Holth et al., 2013; Wang and Mandelkow, 2016; Ali et al., 2019). Endogenous levels of tau also positively correlate with chemically induced seizure susceptibility in wild-type mice (DeVos et al., 2013), suggesting a role of endogenous tau in mediating epileptic activity.

Though not a primary epilepsy, autism spectrum disorder (ASD) is a disease with links to both seizures and tau. Several studies reveal a strong relationship between epilepsy in individuals with autism and autism in those with epilepsy (Viscidi et al., 2013; Reilly et al., 2015; Sundelin et al., 2016), with the prevalence of epilepsy in ASD doubling in adolescence (26%) compared to childhood (12%) (Hara, 2007; Woolfenden et al., 2012; Sharma et al., 2021). Likely explanations supporting the conjugation of the two conditions include an imbalance in neuronal excitation/inhibition (Bourgeron, 2009; Nelson and Valakh, 2015; Specchio et al., 2022). In the Cntnap2^–/– mouse model of autism with focal epilepsy, global tau knockdown prevents epileptic activity in addition to other autistic-like behaviors (Tai et al., 2020), indicating an epileptogenic role of tau in ASD.

Genetic ablation of tau, even by 50% by inactivation of a single Mapt allele, also reduces epileptic activity, high mortality rates, and cognitive deficits in the Scn1a mouse model of Dravet syndrome, a severe and intractable childhood epilepsy that is caused by mutations in the SCN1A gene and can lead to autism (Catterall et al., 2010; Li et al., 2011; Gheyara et al., 2014; Anwar et al., 2019; Tai et al., 2020). This effect also occurs in the Scn1a model following postnatal injection of tau-targeting antisense oligonucleotides (Shao et al., 2022), suggesting that antisense oligonucleotides may be a promising treatment avenue for children with Dravet syndrome. Shao et al. (2022) further found that selective genetic ablation of tau in hippocampal excitatory neurons but not in inhibitory neurons mediates the neuroprotective effects of tau reduction in the Scn1a model. The authors propose that the suppression of epileptic activity by tau reduction may therefore result from a lower hypersynchrony of excitatory neuronal activity rather than greater inhibitory regulation.

In some models, pathological tau, rather than endogenous tau, can contribute to epileptic activity. Temporal lobe epilepsy (TLE) is one of the most prevalent forms of focal epilepsy (Tellez-Zenteno and Hernandez-Ronquillo, 2012; Asadi-Pooya et al., 2017), and in the electrical amygdala kindling rodent model of TLE, tau-knockout mice do not differ from wild-type mice in seizure outcome following repeated kindling (Liu S. et al., 2017). However, kindling produces longer epileptic discharge durations and accelerated seizure progression in rTg4510 transgenic mice, which overexpress P301L tau in forebrain and develop increased p-tau and NFTs (Liu S. et al., 2017). These findings suggest that an increase in p-tau and tau aggregation promotes kindling-induced epileptogenesis.

Taken together, findings across different seizure disease models reveal a significant function of endogenous tau, as well as pathological tau, in the mediation of epileptic activity. Given tau’s role in modulating neuronal activity under normal physiological conditions (DeVos et al., 2013; Chang et al., 2021), endogenous tau likely contributes to network hyperexcitability across primary and secondary epilepsies. In humans, tau mRNA expression and protein levels in the brain can vary greatly (Trabzuni et al., 2012). And though exact reasons for individual differences in endogenous tau levels remain unknown, high levels may consequently predict a person’s susceptibility to epileptic activity. Elevated tau measurements in cerebrospinal fluid have in fact been shown to correlate with seizure type and duration in patients with epilepsy (Tumani et al., 2015). Higher levels of endogenous tau alone may not cause seizures, but it is possible that this may predispose an individual to seizure development upon pathogenesis.

While levels of endogenous or total tau differ across examinations of patients with epilepsy, increased levels of p-tau in the brain are found across many seizure disorders (Thom et al., 2011). These include patients with TLE, Dravet syndrome, Nodding syndrome (Thom et al., 2011; Pollanen et al., 2018; Hotterbeekx et al., 2019), Niemann-Pick type C disease (NPC) (Auer et al., 1995; Love et al., 1995; Suzuki et al., 1995; Malnar et al., 2014), focal cortical dysplasia IIB (FCDIIb) (Sen et al., 2007; Iyer et al., 2014), and tuberous sclerosis complex (TSC) (Sarnat and Flores-Sarnat, 2015; Liu et al., 2020), as well as animal models of post-traumatic epilepsy (PTE) (Cho et al., 2020; Alyenbaawi et al., 2021), Lafora disease (Epm2a^–/–) (Ganesh et al., 2002; Puri et al., 2009; Machado-Salas et al., 2012), and ASD (Gassowska-Dobrowolska et al., 2021). It should be noted that tau aggregation in the brain is associated with older age and is generally uncommon in healthy young adults (Braak et al., 2011; Crary et al., 2014). However, the presence of tau pathology in childhood or adolescent-onset epilepsies, such as Dravet syndrome, Nodding syndrome, Lafora disease, NPC, TSC, and ASD, and in relatively younger TLE patient cohorts (Puvenna et al., 2016; Smith et al., 2019; Gourmaud et al., 2020) suggest a causal link between seizure activity and p-tau accumulation.

In animal models of TLE, tau hyperphosphorylation is observed in relevant brain regions, including the amygdala, hippocampus, and cortex, following chemical and electrical amygdala kindling (Jones et al., 2012; Liu et al., 2016; Alves et al., 2019). And in humans with chronic epilepsy, elevated p-tau is present in post-mortem (Thom et al., 2011) as well as surgically resected tissue (Puvenna et al., 2016; Tai et al., 2016; Liu C. et al., 2017; Prada Jardim et al., 2018; Smith et al., 2019; Gourmaud et al., 2020). For instance, analysis of resected temporal lobe tissue by Tai et al. (2016) found pathological tau phosphorylation in the form of neuropil threads, NFTs, and pre-tangles in 31 of 33 TLE patients between 50 and 65 years of age. Interestingly, observations of subpial bands formed by cortical p-tau depositions have been made across separate studies (Puvenna et al., 2016; Tai et al., 2016; Smith et al., 2019), providing evidence for a novel pattern of tau pathology in TLE that may result from seizure-induced reorganization of temporal lobe networks (Tai et al., 2018).

Tau hyperphosphorylation is also consistently present in the initial and long-term secondary mechanisms initiated by traumatic brain injury (TBI) (Petraglia et al., 2014; Zheng et al., 2014; Rubenstein et al., 2015; Ali et al., 2019; Tan et al., 2020), a leading cause of morbidity and mortality worldwide (Hay et al., 2016). For instance, sustaining even a single TBI can result in progressive NFT formation that is more extensive and severe than what is expected with normal aging (Johnson et al., 2012; Zanier et al., 2018). Furthermore, it is estimated that over 50% of severe TBI cases will result in seizures or PTE (Kovacs et al., 2014), and animal models reveal increased p-tau levels in the brain associated with TBI-induced epileptic activity (Cho et al., 2020; Alyenbaawi et al., 2021). In a recent study, Alyenbaawi et al. (2021) presented a novel model of transgenic zebrafish expressing a fluorescent tau biosensor where TBIs by blast-like pressure waves induced progressive tauopathies. Tau aggregation positively correlated with TBI severity and the presence of seizure-like clonic shaking. Furthermore, tau aggregation following TBI administration was prevented by the anti-convulsant ezogabine and exacerbated by kainate treatment, demonstrating a role of seizure activity in mediating tauopathy development (Alyenbaawi et al., 2021).

A mechanism by which epileptogenesis gives rise to tau hyperphosphorylation may underlie the high incidence of tauopathy and epilepsy co-pathology that is found in diseases such as AD and dementia with Lewy bodies (Vossel et al., 2016, 2017; Beagle et al., 2017). Given that endogenous tau plays a role in regulating neuronal activity, disruption in the homeostatic balance of tau modifications may mediate seizure comorbidities observed in these diseases, and epileptic activity may in turn help drive tau hyperphosophorylation. In classical tauopathies where overt epilepsy infrequently occurs, tau hyperphosphorylation can arise from a variety of different causes (Kovacs, 2017). However, it is also possible that epileptic activity in these tauopathies is clinically underrecognized due to being non-motor or subclinical in nature, as suggested by the detection of subclinical epileptic activity in over 40% of AD patients during overnight electroencephalography and 1-h magnetoencephalogram recordings (Vossel et al., 2016). More studies involving extended periods of neurophysiological monitoring are therefore required to investigate the presence of epileptic activity and its potential contribution to tau hyperphosphorylation in primary tauopathies.

It should also be noted that tau pathology is not universally found in connection with epileptic activity. For instance, 31% of the post-mortem refractory epilepsy cases studied by Thom et al. (2011) were classified as Braak Stage 0, and analysis of surgically resected tissue from 56 TLE patients by Silva et al. (2021) found p-tau-positive neurons in only two samples. The absence of pathological tau deposition in these cases indicates that epileptogenesis does not always lead to tauopathies. However, the factors that determine the subsequent development of tau pathology in some cases of aberrant network excitability but not others remain unclear. It is possible that the formation of pathological tau deposits is linked to specific seizure disorders or that mechanisms mediating tau hyperphosphorylation are overactivated in cases of more severe epilepsy.

Cognitive impairment is a common comorbidity of seizure disorders. Though cognitive deficits can independently occur in seizure disorders as a direct result of disease etiology, such as trauma, epileptic activity contributes to, and exacerbates cognitive decline (Holmes, 2015). However, there are also investigations into a potential role of tau pathology in epilepsy-associated cognitive decline. While individuals with dementia have higher rates of epilepsy, seizures are experienced more frequently in tauopathy-associated dementias like AD than in other dementias (Sanchez et al., 2018). Cognitive decline is also accelerated in patients who have both AD and seizures compared to those with only AD (Vossel et al., 2017), suggesting that pathological tau and seizures can synergistically worsen cognitive outcomes.

Correlations between tau pathology and cognition are in fact observed in epilepsy. Post-mortem analysis of 138 refractory epilepsy cases revealed that 77% of patients with Braak staging III or higher exhibited progressive cognitive decline (Thom et al., 2011), and increased total and p-tau levels measured in surgically resected tissue from TLE patients are inversely correlated with cognitive scores (Kandratavicius et al., 2013; Tai et al., 2016; Gourmaud et al., 2020). In younger TLE patients, an association between post-operative naming decline and subtle tau hyperphosphorylation localized to only the subiculum and dentate gyrus suggest that tau-associated pathological changes in relevant brain regions over time may underlie progressive cognitive impairment seen in TLE (Prada Jardim et al., 2018). Furthermore, the neuroprotective effects of tau ablation against not only seizures but also cognitive deficits in animal models of ASD and Dravet syndrome (Gheyara et al., 2014; Tai et al., 2020) provide evidence for a role of tau in mediating cognitive impairment in these diseases as well. Therefore, tau pathology present in seizure disorders may exacerbate cognitive decline resulting from epileptic states, with seizure-driven tau hyperphosphorylation further compounding this effect with disease progression.

As presented in this review, a mounting body of literature has elucidated connections between tau pathology and epilepsy disorders of diverse etiologies. The antiseizure effect of tau ablation that can be reproduced in a variety of seizure models indicates a significant mediating role of endogenous tau in epileptogenesis. Given findings of upregulated kinase and downregulated phosphatase activity across different seizure disorders, we propose that epileptic activity can trigger homeostatic responses whereby enzymatic pathways disable endogenous tau by increased phosphorylation to stabilize aberrant network hyperexcitability. Subsequent hyperphosphorylation and accumulation of tau results from overactivation of such mechanisms, especially with recurring epileptic activity, and continuous epileptic states. Furthermore, growing evidence indicates a potential contribution of tau hyperphosphorylation to progressive cognitive decline in seizure disorders. Though the exact degrees to which tau involvement in seizures and cognitive decline are mediated by convergent or divergent mechanisms in distinct diseases remains unclear, the overlapping of tau-related cell signaling pathways and prevalence of tau hyperphosphorylation found throughout different types of epilepsies (Table 1) warrant continuing efforts into understanding epilepsies from a tauopathy perspective. Greater focus on tau in epileptic pathophysiology may yield advances in diagnostic and prognostic tools and novel therapeutic approaches targeting tau and tau-associated pathways.

KV and KH developed the manuscript concept. KH prepared the figure and table. All authors contributed to the manuscript and approved the final submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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