Preprint Article Version 2 Preserved in Portico This version is not peer-reviewed

Lamotrigine Attenuates Neuronal Excitability, Depresses GABA Synaptic Inhibition, and Modulates Theta Rhythms in Rat Hippocampus

Version 1 : Received: 1 November 2021 / Approved: 3 November 2021 / Online: 3 November 2021 (08:46:06 CET)
Version 2 : Received: 4 November 2021 / Approved: 5 November 2021 / Online: 5 November 2021 (11:31:29 CET)

How to cite: Kazmierska-Grebowska, P.; Siwiec, M.; Sowa, J.E.; Caban, B.; Kowalczyk, T.; Bocian, R.; MacIver, M.B. Lamotrigine Attenuates Neuronal Excitability, Depresses GABA Synaptic Inhibition, and Modulates Theta Rhythms in Rat Hippocampus. Preprints 2021, 2021110067 (doi: 10.20944/preprints202111.0067.v2). Kazmierska-Grebowska, P.; Siwiec, M.; Sowa, J.E.; Caban, B.; Kowalczyk, T.; Bocian, R.; MacIver, M.B. Lamotrigine Attenuates Neuronal Excitability, Depresses GABA Synaptic Inhibition, and Modulates Theta Rhythms in Rat Hippocampus. Preprints 2021, 2021110067 (doi: 10.20944/preprints202111.0067.v2).

Abstract

Theta oscillations generated in hippocampal (HPC) and cortical neuronal networks are involved in various aspects of brain function, including sensorimotor integration, movement planning, memory formation and attention. Disruptions of theta rhythms are present in individuals with various disorders, including epilepsy and Alzheimer’s disease. Theta rhythm generation involves a specific interplay between cellular (ionic) and network (synaptic) mechanisms. HCN channels are theta modulators, and several medications are known to enhance their activity. We investigated how different doses of lamotrigine (LTG), an HCN channel activator, and antiepileptic and neuroprotective agent, would affect hippocampal theta rhythms in acute HPC slices (in vitro) and anaesthetized rats (in vivo). Whole-cell patch clamp recordings revealed that LTG decreased GABAA-fast transmission in CA3 and CA1 cells, in vitro. In addition, LTG directly depressed CA3 and CA1 pyramidal neuron excitability. These effects were partially blocked by ZD 7288, a selective HCN blocker, and are consistent with decreased excitability associated with antiepileptic actions. Lamotrigine also depressed hippocampal theta oscillations in vitro, also consistent with its neuronal depressant effects. In contrast, it exerted an opposite, enhancing effect, on theta recorded in vivo. The contradictory in vivo and in vitro results indicate that LTG increases ascending theta activating medial septum/entorhinal synaptic inputs that over-power the depressant effects seen in hippocampal neurons. These results provide new insights into LTG actions and indicate an opportunity to develop more precise therapeutics for the treatment of dementias, memory disorders and epilepsy.

Keywords

Ih current, lamotrigine, HCN channels, theta rhythm, local field potentials, IPSCs, membrane excitability, action potential, membrane resonance.)

Subject

MEDICINE & PHARMACOLOGY, Pharmacology & Toxicology

Comments (1)

Comment 1
Received: 5 November 2021
Commenter: M. Bruce MacIver
Commenter's Conflict of Interests: Author
Comment: Corrected Author Names and addresses.
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