Perturbed Information Processing Complexity in Experimental Epilepsy.

Comorbidities, such as cognitive deficits, which often accompany epilepsies, constitute a basal state, while seizures are rare and transient events. This suggests that neural dynamics, in particular those supporting cognitive function, are altered in a permanent manner in epilepsy. Here, we test the hypothesis that primitive processes of information processing at the core of cognitive function (i.e., storage and sharing of information) are altered in the hippocampus and the entorhinal cortex in experimental epilepsy in adult, male Wistar rats. We find that information storage and sharing are organized into substates across the stereotypic states of slow and theta oscillations in both epilepsy and control conditions. However, their internal composition and organization through time are disrupted in epilepsy, partially losing brain state selectivity compared with controls, and shifting toward a regimen of disorder. We propose that the alteration of information processing at this algorithmic level of computation, the theoretical intermediate level between structure and function, may be a mechanism behind the emergent and widespread comorbidities associated with epilepsy, and perhaps other disorders.SIGNIFICANCE STATEMENT Comorbidities, such as cognitive deficits, which often accompany epilepsies, constitute a basal state, while seizures are rare and transient events. This suggests that neural dynamics, in particular those supporting cognitive function, are altered in a permanent manner in epilepsy. Here, we show that basic processes of information processing at the core of cognitive function (i.e., storage and sharing of information) are altered in the hippocampus and the entorhinal cortex (two regions involved in memory processes) in experimental epilepsy. Such disruption of information processing at the algorithmic level itself could underlie the general performance impairments in epilepsy.

Transient demyelination causes long-term cognitive impairment, myelin alteration and network synchrony defects.

In the adult brain, activity-dependent myelin plasticity is required for proper learning and memory consolidation. Myelin loss, alteration, or even subtle structural modifications can therefore compromise the network activity, leading to functional impairment. In multiple sclerosis, spontaneous myelin repair process is possible, but it is heterogeneous among patients, sometimes leading to functional recovery, often more visible at the motor level than at the cognitive level. In cuprizone-treated mouse model, massive brain demyelination is followed by spontaneous and robust remyelination. However, reformed myelin, although functional, may not exhibit the same morphological characteristics as developmental myelin, which can have an impact on the activity of neural networks. In this context, we used the cuprizone-treated mouse model to analyze the structural, functional, and cognitive long-term effects of transient demyelination. Our results show that an episode of demyelination induces despite remyelination long-term cognitive impairment, such as deficits in spatial working memory, social memory, cognitive flexibility, and hyperactivity. These deficits were associated with a reduction in myelin content in the medial prefrontal cortex (mPFC) and hippocampus (HPC), as well as structural myelin modifications, suggesting that the remyelination process may be imperfect in these structures. In vivo electrophysiological recordings showed that the demyelination episode altered the synchronization of HPC-mPFC activity, which is crucial for memory processes. Altogether, our data indicate that the myelin repair process following transient demyelination does not allow the complete recovery of the initial myelin properties in cortical structures. These subtle modifications alter network features, leading to prolonged cognitive deficits in mice.

Spatio-temporal heterogeneity in hippocampal metabolism in control and epilepsy conditions.

The hippocampus's dorsal and ventral parts are involved in different operative circuits, the functions of which vary in time during the night and day cycle. These functions are altered in epilepsy. Since energy production is tailored to function, we hypothesized that energy production would be space- and time-dependent in the hippocampus and that such an organizing principle would be modified in epilepsy. Using metabolic imaging and metabolite sensing ex vivo, we show that the ventral hippocampus favors aerobic glycolysis over oxidative phosphorylation as compared to the dorsal part in the morning in control mice. In the afternoon, aerobic glycolysis is decreased and oxidative phosphorylation increased. In the dorsal hippocampus, the metabolic activity varies less between these two times but is weaker than in the ventral. Thus, the energy metabolism is different along the dorsoventral axis and changes as a function of time in control mice. In an experimental model of epilepsy, we find a large alteration of such spatiotemporal organization. In addition to a general hypometabolic state, the dorsoventral difference disappears in the morning, when seizure probability is low. In the afternoon, when seizure probability is high, the aerobic glycolysis is enhanced in both parts, the increase being stronger in the ventral area. We suggest that energy metabolism is tailored to the functions performed by brain networks, which vary over time. In pathological conditions, the alterations of these general rules may contribute to network dysfunctions.

Deficit in observational learning in experimental epilepsy.

Individuals use the observation of a conspecific to learn new behaviors and skills in many species. Whether observational learning is affected in epilepsy is not known. Using the pilocarpine rat model of epilepsy, we assessed learning by observation in a spatial task. The task involves a naive animal observing a demonstrator animal seeking a reward at a specific spatial location. After five observational sessions, the observer is allowed to explore the rewarded space and look for the reward. Although control observer rats succeed in finding the reward when allowed to explore the rewarded space, epileptic animals fail. However, epileptic animals are able to successfully learn the location of the reward through their own experience after several trial sessions. Thus, epileptic animals show a clear deficit in learning by observation. This result may be clinically relevant, in particular in children who strongly rely on observational learning.

Cell Assemblies in the Cortico-Hippocampal-Reuniens Network during Slow Oscillations.

The nucleus reuniens (NR) is an important anatomic and functional relay between the medial prefrontal cortex (mPFC) and the hippocampus (HPC). Whether the NR controls neuronal assemblies, a hallmark of information exchange between the HPC and mPFC for memory transfer/consolidation, is not known. Using simultaneous local field potential and unit recordings in NR, HPC, and mPFC in male rats during slow oscillations under anesthesia, we identified a reliable sequential activation of NR neurons at the beginning of UP states, which preceded mPFC ones. NR sequences were spatially organized, from dorsal to ventral NR. Chemical inactivation of the NR disrupted mPFC sequences at the onset of UP states as well as HPC sequences present during sharp-wave ripples. We conclude that the NR contributes to the coordination and stabilization of mPFC and HPC neuronal sequences during slow oscillations, possibly via the early activation of its own sequences.SIGNIFICANCE STATEMENT Neuronal assemblies are believed to be instrumental to code/encode/store information. They can be recorded in different brain regions, suggesting that widely distributed networks of networks are involved in such information processing. The medial prefrontal cortex, the hippocampus, and the thalamic nucleus reuniens constitute a typical example of a complex network involved in memory consolidation. In this study, we show that spatially organized cells assemblies are recruited in the nucleus reuniens at the UP state onset during slow oscillations. Nucleus reuniens activity appears to be necessary to the stability of medial prefrontal cortex and hippocampal cell assembly formation during slow oscillations. This result further highlights the role of the nucleus reuniens as a functional hub for exchanging and processing memories.

Antiseizure effects of Anacyclus pyrethrum in socially isolated rats with and without a positive handling strategy.

OBJECTIVE: Aqueous extract of Anacyclus pyrethrum (AEAPR) is used in traditional medicine to treat epilepsy, but whether it has antiseizure properties has not been established. Because extracts of the plant have antioxidant properties, we hypothesized that it may be particularly potent in conditions associated with oxidative stress, in particular social isolation. METHODS: We addressed these objectives in the pilocarpine experimental model of epilepsy using socially isolated rats maintaining contacts with (handled) and without (unhandled) positive handling strategy. Both groups were further divided into treated (AEAPR was added to the drinking water) and untreated groups. Continuous (24/7) electroencephalography (EEG) recordings started in the sixth week after status epilepticus (SE) with a predrug control period of 3 weeks, followed by 3 weeks of daily treatment with AEAPR or water, and finally a postdrug control period of 3 weeks. At the end of the experimental procedure, we measured lipid peroxidation, superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase activities in the hippocampus to assess oxidative stress. RESULTS: A. pyrethrum treatment significantly reduced seizure frequency by 51% and 57%, duration by 30% and 33%, and severity by 31% and 26% in isolated handled and unhandled rats, respectively. The beneficial effects on seizures were still present 3 weeks after the end of the treatment. The treatment reduced lipid peroxidation as well as SOD, GPx, and catalase activities. SIGNIFICANCE: We conclude that A. pyrethrum has antiseizure and antioxidant properties, even in social isolation conditions.

The Nucleus Reuniens Controls Long-Range Hippocampo-Prefrontal Gamma Synchronization during Slow Oscillations.

Gamma oscillations are involved in long-range coupling of distant regions that support various cognitive operations. Here we show in adult male rats that synchronized bursts of gamma oscillations bind the hippocampus (HPC) and prefrontal cortex (mPFC) during slow oscillations and slow-wave sleep, a brain state that is central for consolidation of memory traces. These gamma bursts entrained the firing of the local HPC and mPFC neuronal populations. Neurons of the nucleus reuniens (NR), which is a structural and functional hub between HPC and mPFC, demonstrated a specific increase in their firing before gamma burst onset, suggesting their involvement in HPC-mPFC binding. Chemical inactivation of NR disrupted the temporal pattern of gamma bursts and their synchronization, as well as mPFC neuronal firing. We propose that the NR drives long-range hippocampo-prefrontal coupling via gamma bursts providing temporal windows for information exchange between the HPC and mPFC during slow-wave sleep.SIGNIFICANCE STATEMENT Long-range coupling between hippocampus (HPC) and prefrontal cortex (mPFC) is believed to support numerous cognitive functions, including memory consolidation occurring during sleep. Gamma-band synchronization is a fundamental process in many neuronal operations and is instrumental in long-range coupling. Recent evidence highlights the role of nucleus reuniens (NR) in consolidation; however, how it influences hippocampo-prefrontal coupling is unknown. In this study, we show that HPC and mPFC are synchronized by gamma bursts during slow oscillations in anesthesia and natural sleep. By manipulating and recording the NR-HPC-mPFC network, we provide evidence that the NR actively promotes this long-range gamma coupling. This coupling provides the hippocampo-prefrontal circuit with a novel mechanism to exchange information during slow-wave sleep.

Antioxidant treatment after epileptogenesis onset prevents comorbidities in rats sensitized by a past stressful event.

OBJECTIVE: Unresolved past stressful events can induce a state of vulnerability to epilepsy and comorbidities. Using an experimental model of stress-induced vulnerability to depression, we tested whether an antioxidant treatment applied after the onset of epileptogenesis was disease modifying and could prevent the occurrence of comorbidities. METHODS: We used social defeat (SD) to trigger a state of vulnerability in half of the SD-exposed population of rats. One month after SD, we used repeated injections of kainic acid to trigger status epilepticus (SE). One subset of animals was treated after SE during 2 weeks with Tempol, a strong antioxidant. Supradural 24/7 recordings were used to assess the development of epilepsy. We assessed spatial and nonspatial memory as well as a depressionlike profile 6 weeks after SE. RESULTS: Serum brain-derived neurotrophic factor (BDNF) levels decreased after SD in all animals and recovered to pre-SD levels 1 month later in half of them (SDN group). The other half kept low serum BDNF levels (SDL group). At that stage, SDN and SDL animals do not present a depressionlike profile. The SDL group was more sensitive than the SDN group to epileptogenic conditions. Following SE, the SDL group displayed accelerated epileptogenesis, a depressionlike profile, and severe cognitive deficits as compared to SDN rats. Transient Tempol treatment was disease-modifying, reducing the number of seizures, and prevented the development of comorbidities in the SDL group. Tempol treatment normalized oxidative stress in the SDL group to SDN levels. SIGNIFICANCE: This study illustrates the disease-modifying effect of antioxidant treatment after the onset of epileptogenesis in a population rendered vulnerable by past stressful events. The transient treatment decreased seizure burden and had long-term effects, preventing the occurrence of a depressionlike profile and cognitive deficits. We propose that vulnerability to comorbidities can be reversed after the onset of epilepsy.

Interneurons contribute to the hemodynamic/metabolic response to epileptiform discharges.

Interpretation of hemodynamic responses in epilepsy is hampered by an incomplete understanding of the underlying neurovascular coupling, especially the contributions of excitation and inhibition. We made simultaneous multimodal recordings of local field potentials (LFPs), firing of individual neurons, blood flow, and oxygen level in the somatosensory cortex of anesthetized rats. Epileptiform discharges induced by bicuculline injections were used to trigger large local events. LFP and blood flow were robustly coupled, as were LFP and tissue oxygen. In a parametric linear model, LFP and the baseline activities of cerebral blood flow and tissue partial oxygen tension contributed significantly to blood flow and oxygen responses. In an analysis of recordings from 402 neurons, blood flow/tissue oxygen correlated with the discharge of putative interneurons but not of principal cells. Our results show that interneuron activity is important in the vascular and metabolic responses during epileptiform discharges.

Predicting and treating stress-induced vulnerability to epilepsy and depression.

Accumulation of stressful events can render individuals susceptible to develop epilepsy and comorbidities. Whether such vulnerability can be predicted and reversed is not known. Here we show that social defeat, although not producing depression by itself, produced in 50% of rats reduced threshold for status epilepticus (SE), accelerated epileptogenesis, and once epilepsy was induced, depression-like profile and cognitive deficits. Low serum brain-derived neurotrophic factor (BDNF) levels measured before SE identified this vulnerable population. Treatment with a BDNF analog before SE prevented the occurrence of comorbidities. Thus, vulnerability to comorbidities after epilepsy onset due to unresolved past stressful events may be predicted and reversed.

Recovery of brain biomarkers following peroxisome proliferator-activated receptor agonist neuroprotective treatment before ischemic stroke.

BACKGROUND: Lipid lowering agent such as agonists of peroxisome proliferator-activated receptors (PPAR) are suggested as neuroprotective agents and may protect from the sequelae of brain ischemic stroke. Although the demonstration is not clearly established in human, the underlying molecular mechanism may be of interest for future therapeutic purposes. To this end, we have used our well established rodent model of ischemia-reperfusion pre-treated or not with fenofibrate or atorvastatin and performed a differential proteomics analyses of the brain and analysed the protein markers which levels returned to "normal" following pre-treatments with PPARα agonists. RESULTS: In order to identify potential therapeutic targets positively modulated by pre-treatment with the PPARα agonists, two-dimensional gel electrophoresis proteome profiles between control, ischemia-reperfusion and pre-treated or not, were compared. The polypeptide which expression was altered following ischemia - reperfusion but whose levels remain unchanged after pre-treatment were characterized by mass spectrometry and further investigated by Western-blotting and immunohistochemistry. A series of 28 polypeptides were characterized among which the protein disulfide isomerase reduction - a protein instrumental to the unfolded protein response system - was shown to be reduced following PPARα agonists treatment while it was strongly increased in ischemia-reperfusion. CONCLUSIONS: Pre-treatment with PPARα agonist or atorvastatin show potential neuroprotective effects by inhibiting the PDI overexpression in conjunction with the preservation of other neuronal markers, several of which are associated with the regulation of protein homeostasis, signal transduction and maintenance of synaptic plasticity. This proteomic study therefore suggests that neuroprotective effect of PPARα agonists supposes the preservation of the expression of several proteins essential for the maintenance of protein homeostasis not necessarily directly linked to PPARα known-regulated targets.

Changes in interictal spike features precede the onset of temporal lobe epilepsy.

OBJECTIVE: One cornerstone event during epileptogenesis is the occurrence of the first spontaneous seizure (SZ1). It is therefore important to identify biomarkers of the network alterations leading to SZ1. In experimental models of temporal lobe epilepsy (TLE), interictal-like activity (ILA) precedes SZ1 by several days. The goal of this study was to determine whether ILA dynamics bore electrophysiological features signaling the impeding transition to SZ1. METHODS: Experimental TLE was triggered by pilocarpine- or kainic acid-induced status epilepticus (SE). Continuous electroencephalographic recordings were performed 7 days before and up to 40 days after SE. The amplitude and duration of the spike and wave components of interictal spikes were analyzed. RESULTS: Two types of interictal spikes were distinguished: type 1, with a spike followed by a long-lasting wave, and type 2, with a spike without wave. The number, amplitude, and duration of type 1 spikes started to decrease, whereas the number of type 2 spikes increased, several days before SZ1, reaching their minimum/maximum values just before SZ1. INTERPRETATION: The change in ILA pattern could constitute a predictive biomarker of SZ1. The mechanisms underlying these dynamic modifications and their functional impact are discussed in the context of the construction of an epileptogenic network.

Long-term near-continuous recording with Neuropixels probes in healthy and epileptic rats.

Neuropixels probes have become a crucial tool for high-density electrophysiological recordings. Although most research involving these probes is in acute preparations, some scientific inquiries require long-term recordings in freely moving animals. Recent reports have presented prosthesis designs for chronic recordings, but some of them do not allow for probe recovery, which is desirable given their cost. Others appear to be fragile, as these articles describe numerous broken implants.Objective.This fragility presents a challenge for recordings in rats, particularly in epilepsy models where strong mechanical stress impinges upon the prosthesis. To overcome these limitations, we sought to develop a new prosthesis for long-term electrophysiological recordings in healthy and epileptic rats.Approach.We present a new prosthesis specifically designed to protect the probes from strong shocks and enable the safe retrieval of probes after experiments.Main results.This prosthesis was successfully used to record from healthy and epileptic rats for up to three weeks almost continuously. Overall, 10 out of 11 probes could be successfully retrieved with a retrieval and reuse success rate of 91%.Significance.Our design and protocol significantly improved previously described probe recycling performances and prove usage on epileptic rats.

Sleep biomarkers for stress-induced vulnerability to depression.

Stress can push individuals close to the threshold to depression. An individual's intrinsic vulnerability before a stressful event determines how close they come to the threshold of depression. Identification of vulnerability biomarkers at early (before the stressful event) and late (close to the threshold after the stressful event) stages would allow for corrective actions. Social defeat is a stressful event that triggers vulnerability to depression in half of exposed rats. We analyzed the sleep properties of rats before (baseline) and after (recovery) social defeat by telemetry electroencephalogram recordings. Using Gaussian partitioning, we identified three non-rapid eye movement stages (N-S1, N-S2, and N-S3) in rats based on a sleep depth index (relative δ power) and a cortical activity index (fractal dimension). We found (1) that, at baseline, N-S3 lability and high-θ relative power in wake identified, with 82% accuracy, the population of rats that will become vulnerable to depression after social defeat, and (2) that, at recovery, N-S1 instability identified vulnerable rats with 83% accuracy. Thus, our study identified early and late sleep biomarkers of vulnerability to depression, opening the way to the development of treatments at a prodromal stage for high sensitivity to stress, and for stress-induced vulnerability to depression.

Neuron-restrictive silencer factor-mediated hyperpolarization-activated cyclic nucleotide gated channelopathy in experimental temporal lobe epilepsy.

OBJECTIVE: Enduring, abnormal expression and function of the ion channel hyperpolarization-activated cyclic adenosine monophosphate gated channel type 1 (HCN1) occurs in temporal lobe epilepsy (TLE). We examined the underlying mechanisms, and investigated whether interfering with these mechanisms could modify disease course. METHODS: Experimental TLE was provoked by kainic acid-induced status epilepticus (SE). HCN1 channel repression was examined at mRNA, protein, and functional levels. Chromatin immunoprecipitation was employed to identify the transcriptional mechanism of repressed HCN1 expression, and the basis for their endurance. Physical interaction of the repressor, NRSF, was abolished using decoy oligodeoxynucleotides (ODNs). Video/electroencephalographic recordings were performed to assess the onset and initial pattern of spontaneous seizures. RESULTS: Levels of NRSF and its physical binding to the Hcn1 gene were augmented after SE, resulting in repression of HCN1 expression and HCN1-mediated currents (I(h) ), and reduced I(h) -dependent resonance in hippocampal CA1 pyramidal cell dendrites. Chromatin changes typical of enduring, epigenetic gene repression were apparent at the Hcn1 gene within a week after SE. Administration of decoy ODNs comprising the NRSF DNA-binding sequence (neuron restrictive silencer element [NRSE]), in vitro and in vivo, reduced NRSF binding to Hcn1, prevented its repression, and restored I(h) function. In vivo, decoy NRSE ODN treatment restored theta rhythm and altered the initial pattern of spontaneous seizures. INTERPRETATION: Acquired HCN1 channelopathy derives from NRSF-mediated transcriptional repression that endures via chromatin modification and may provide insight into the mechanisms of a number of channelopathies that coexist with, and may contribute to, the conversion of a normal brain into an epileptic one.

In Vivo Characterization of Neurophysiological Diversity in the Lateral Supramammillary Nucleus during Hippocampal Sharp-wave Ripples of Adult Rats.

The extent of the networks that control the genesis and modulation of hippocampal sharp-wave ripples (SPW-Rs), which are involved in memory consolidation, remains incompletely understood. Here, we performed a detailed in vivo analysis of single cell firing in the lateral supramammillary nucleus (lSuM) during theta and slow oscillations, including SPW-Rs, in anesthetized rats. We classified neurons as SPW-R-active and SPW-R-unchanged according to whether or not they increased their firing during SPW-Rs. We show that lSuM SPW-R-active neurons increase their firing prior to SPW-Rs peak power and prior to hippocampal excitatory cell activation. Moreover, lSuM SPW-R-active neurons show increased firing activity during theta and slow oscillations as compared to unchanged neurons. These results suggest that a sub-population of lSuM neurons can interact with the hippocampus during SPW-Rs, raising the possibility that the lSuM may modulate memory consolidation.

Targeted Transgene Expression in Cholinergic Interneurons in the Monkey Striatum Using Canine Adenovirus Serotype 2 Vectors.

The striatum, the main input structure of the basal ganglia, is critical for action selection and adaptive motor control. To understand the neuronal mechanisms underlying these functions, an analysis of microcircuits that compose the striatum is necessary. Among these, cholinergic interneurons (ChIs) provide intrinsic striatal innervation whose dysfunction is implicated in neuropsychiatric diseases, such as Parkinson's disease and Tourette syndrome. The ability to experimentally manipulate the activity of ChIs is critical to gain insights into their contribution to the normal function of the striatum and the emergence of behavioral abnormalities in pathological states. In this study, we generated and tested CAV-pChAT-GFP, a replication-defective canine adenovirus type 2 (CAV-2) vector carrying the green fluorescent protein (GFP) sequence under the control of the human choline acetyltransferase (ChAT) promoter. We first tested the potential specificity of CAV-pChAT-GFP to label striatal ChIs in a rat before performing experiments on two macaque monkeys. In the vector-injected rat and monkey striatum, we found that GFP expression preferentially colocalized with ChAT-immunoreactivity throughout the striatum, including those from local circuit interneurons. CAV-2 vectors containing transgene driven by the ChAT promoter provide a powerful tool for investigating ChI contributions to circuit function and behavior in nonhuman primates.

GABA-glutamate supramammillary neurons control theta and gamma oscillations in the dentate gyrus during paradoxical (REM) sleep.

Several studies suggest that neurons from the lateral region of the SuM (SuML) innervating the dorsal dentate gyrus (DG) display a dual GABAergic and glutamatergic transmission and are specifically activated during paradoxical (REM) sleep (PS). The objective of the present study is to characterize the anatomical, neurochemical and electrophysiological properties of the SuML-DG projection neurons and to determine how they control DG oscillations and neuronal activation during PS and other vigilance states. For this purpose, we combine structural connectivity techniques using neurotropic viral vectors (rabies virus, AAV), neurochemical anatomy (immunohistochemistry, in situ hybridization) and imaging (light, electron and confocal microscopy) with in vitro (patch clamp) and in vivo (LFP, EEG) optogenetic and electrophysiological recordings performed in transgenic VGLUT2-cre male mice. At the cellular level, we show that the SuML-DG neurons co-release GABA and glutamate on dentate granule cells and increase the activity of a subset of DG granule cells. At the network level, we show that activation of the SuML-DG pathway increases theta power and frequency during PS as well as gamma power during PS and waking in the DG. At the behavioral level, we show that the activation of this pathway does not change animal behavior during PS, induces awakening during slow wave sleep and increases motor activity during waking. These results suggest that the SuML-DG pathway is capable of supporting the increase of theta and gamma power in the DG observed during PS and plays an important modulatory role of DG network activity during this state.

Endogenous multidien rhythm of epilepsy in rats.

Recent trials of chronic EEG in humans showed that epilepsy is a cyclical disorder of the brain with rhythms at multiple time-scales: circadian, multi-day (multidien) or even seasonal. Here, we analyzed chronic EEG data (>30 days) in male epileptic rats and unraveled not only circadian but also, slower, multidien rhythms of interictal epileptiform activity with periodicity of about 2-3 and 5-7 days. Importantly, seizures were not uniformly distributed over time, but rather clustered at preferential phases of these underlying rhythms, delineating critical circadian times and multidien phase of heightened seizure risk. Multidien rhythms were not synchronous across animals or with human intervention suggesting an endogenous generator. In epilepsy, across species, unknown factors modulate seizure timing in cyclical patterns over multiple days.

Caffeine Consumption During Pregnancy Accelerates the Development of Cognitive Deficits in Offspring in a Model of Tauopathy.

Psychoactive drugs used during pregnancy can affect the development of the brain of offspring, directly triggering neurological disorders or increasing the risk for their occurrence. Caffeine is the most widely consumed psychoactive drug, including during pregnancy. In Wild type mice, early life exposure to caffeine renders offspring more susceptible to seizures. Here, we tested the long-term consequences of early life exposure to caffeine in THY-Tau22 transgenic mice, a model of Alzheimer's disease-like Tau pathology. Caffeine exposed mutant offspring developed cognitive earlier than water treated mutants. Electrophysiological recordings of hippocampal CA1 pyramidal cells in vitro revealed that early life exposure to caffeine changed the way the glutamatergic and GABAergic drives were modified by the Tau pathology. We conclude that early-life exposure to caffeine affects the Tau phenotype and we suggest that caffeine exposure during pregnancy may constitute a risk-factor for early onset of Alzheimer's disease-like pathology.