CHEMOGENETIC MODULATION OF ASTROCYTES IN A MODEL FOR TEMPORAL LOBE EPILEPSY

Research output: Unpublished contribution to conferencePoster

Abstract

Temporal lobe epilepsy (TLE) is an acquired form of focal epilepsy, in which patients suffer from unprovoked, devastating seizures. In one-third of the patients the available anti-seizure drugs, which are mainly focused on neuronal targets, do not adequately control seizures, emphasizing the need for novel treatment strategies. More recently, the crucial role of astrocytes, the most abundant cell-type in the central nervous system, in TLE has been acknowledged. Reactive astrogliosis, characterized by morphological and molecular changes in astrocyte phenotype, is one of the hallmarks of TLE. They exhibit multiple changes in transporter- and enzyme expression, underlying epileptic hyperexcitability. For instance, during epileptiform activity, significant elevations in the frequency of Ca2+ oscillations have been observed in brain slices as well as in vivo. These Ca2+-waves lead to astrocytic glutamate release, which in turn favor synchronized neuronal activation. Moreover, astrocytes play a key role in cognition, which is often severely affected TLE-patients.

We use a clinically relevant mouse model for TLE, the intrahippocampal kainic acid mouse model, achieved by unilateral kainic acid injection in the hippocampus of the mouse brain. The mice immediately enter a status epilepticus and develop spontaneous limbic seizures after a latency period of 2 weeks. First, we validated the mouse model for TLE and the related cognitive comorbidity. To this end we use in vivo EEG-monitoring and a test for spatial learning and memory, the Barnes maze test. On average, we have found that 36 ± 5,643 epileptic discharges per hour occurred (n = 7). In the Barnes maze test we demonstrated that the epileptic mice understand the paradigm context, but perform significantly worse compared to naive and sham control mice. Moreover, epileptic mice did not adopt the efficient, hippocampus-dependent spatial search strategy, but used a less-efficient serial search strategy, resulting in poorer task performance (i.e. longer escape-latencies and higher amounts of errors).

As a next step, we will use a chemogenetic approach to selectively address the role of astrocyte signalling in TLE. To obtain astrocyte-specific modulation, hippocampal astrocytes are transfected with designer receptors exclusively activated by designer drugs (DREADDs), allowing us to evaluate the effect of astrocyte-specific modulation on the recurrence of spontaneous seizures and the associated comorbidities. To assure DREADD-functionality, we will perform ex vivo slice electrophysiology, ex vivo calcium imaging and immunohistochemistry experiments. As a final step, the effect of DREADD-transfected astrocytes on seizures and comorbidities will be determined.
Original languageEnglish
Publication statusPublished - 24 May 2019
EventBelgian Society for Neuroscience (BSN) Congress 2019 - Palace of the Academies, Brussels, Belgium
Duration: 24 May 2019 → …

Conference

ConferenceBelgian Society for Neuroscience (BSN) Congress 2019
CountryBelgium
CityBrussels
Period24/05/19 → …

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