Tau is a microtubule-associated protein known to bind and promote assembly of microtubules in neurons under physiological conditions. However, under pathological conditions, aggregation of hyperphosphorylated tau causes neuronal toxicity, neurodegeneration, and resulting tauopathies like Alzheimer’s disease (AD). Clinically, patients with tauopathies present with either dementia, movement disorders, or a combination of both. The deposition of hyperphosphorylated tau in the brain is also associated with epilepsy and network hyperexcitability in a variety of neurological diseases. Furthermore, pharmacological and genetic targeting of tau-based mechanisms can have anti-seizure effects. Suppressing tau phosphorylation decreases seizure activity in acquired epilepsy models while reducing or ablating tau attenuates network hyperexcitability in both Alzheimer’s and epilepsy models. However, it remains unclear whether tauopathy and epilepsy comorbidities are mediated by convergent mechanisms occurring upstream of epileptogenesis and tau aggregation, by feedforward mechanisms between the two, or simply by coincident processes. In this review, we investigate the relationship between tauopathies and seizure disorders, including temporal lobe epilepsy (TLE), post-traumatic epilepsy (PTE), autism spectrum disorder (ASD), Dravet syndrome, Nodding syndrome, Niemann-Pick type C disease (NPC), Lafora disease, focal cortical dysplasia, and tuberous sclerosis complex. We also explore potential mechanisms implicating the role of tau kinases and phosphatases as well as the mammalian target of rapamycin (mTOR) in the promotion of co-pathology. Understanding the role of these co-pathologies could lead to new insights and therapies targeting both epileptogenic mechanisms and cognitive decline.

Adolescent exposure to caffeine has been shown to decrease immobility in the forced swim test, suggesting and antidepressant-like effect of caffeine; however, studies have produced different results with regard to caffeine-induced active behaviors. The present study attempted to clarify the possible neurochemical mechanisms of caffeine’s action by selectively depleting norepinephrine with alpha-methyl-p-tyrosine or serotonin with para-chlorophenylalanine in two separate experiments and assessing the ability for caffeine to alter anxiety-like and depressive-like behavior. Caffeine-treated adolescent male rats were exposed to caffeine (0.25 g/L) in their drinking water beginning on P28. A-methyl-p-tyrosine, para-chlorophenylalanine, or saline were administered prior to light-dark, open field, and forced swim testing beginning on P45. Caffeine-induced reductions in immobility and increases in swimming in the forced swim test were reversed by both a-methyl-p-tyrosine and para-chlorophenylalanine. Caffeine-induced increases in crosses and rears were reversed by para-chlorophenylalanine but not alpha-methyl-p-tyrosine, whereas caffeine-induced increases in transitions in the LD test were reversed by alpha-methyl-p-tyrosine but not para-chlorophenylalanine. Taken together, these results suggest that caffeine-induced decreases in immobility in male rats requires both norepinephrine and serotonin as depletion of either prevents the induction of immobility by chronic caffeine.

BackgroundAbnormal α‐synuclein (αS) plays an important role in the pathology of Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). New evidence shows network hyperexcitability can accelerate synaptic and cognitive deficits in PDD and DLB. While 90% of epileptiform activity is detected during sleep in Alzheimer’s disease (AD), epileptiform activity during sleep in PDD or DLB is poorly understood. There are currently no known treatments to delay PDD or DLB progression. Although antiseizure drugs (ASDs) have been used to improve memory deficits in AD, this treatment approach has not been investigated in α‐synucleinopathies.MethodsTo explore the effect of ASDs in attenuating αS‐dependent seizure activity, we used transgenic mice expressing the A53T mutant human α‐synuclein (TgA53T) as a model of motor and cognitive decline in PDD and DLB. We have begun screening FDA‐approved ASDs using cortical electroencephalography with electromyography to examine epileptic events 24 hours before and after intraperitoneal injection. The two ASDs exhibiting the strongest efficacy in reducing epileptic activity across sleep‐wake states will be tested for effects on cognitive function and synaptic plasticity following chronic administration. We are also quantifying pathological high frequency network oscillations (HFOs), biomarkers of epileptogenesis.Results3‐4‐month‐old TgA53T mice experienced epileptiform events but had normal long‐term potentiation (LTP) and memory, indicating that epileptic activity onset precedes αS‐induced synaptic and cognitive deficits. Starting at 6 months of age, TgA53T hippocampal slices show the absence of LTP, with reduced c‐fos and calbindin and increased neuropeptide Y indicating alterations in hippocampal inhibitory circuitry. In behavioral testing, TgA53T mice exhibit impairment in fear conditioning, Y‐maze spatial recognition, and Barnes maze spatial learning and memory with age. Preliminary studies indicate lacosamide and brivaracetam as the most effective of ASDs tested in reducing epileptic myoclonus and interictal epileptiform events. We also found more HFOs in TgA53T mice and TgA53T mice with tau ablation.ConclusionSuppression of epileptic activity by ASDs would support ASDs as a novel treatment for reducing or preventing cognitive dysfunction in DLB and PDD. Furthermore, ASD‐induced reversal of synaptic and cognitive deficits would provide evidence that epileptic activity plays a causal role in αS‐dependent pathology.