Lamotrigine Restores Impairments in Theta Rhythms and LTP as Early Biomarkers of Aβ_1-42-Induced Hippocampal Network...

Neuronal excitation/inhibition (E/I) imbalance, epileptiform activity, and synaptic dysfunction are present in individuals diagnosed with dementia, including sporadic Alzheimer's disease (sAD), even at early stages. These abnormalities are associated with altered neuronal oscillatory activity, as seen in EEG recordings of sAD patients and transgenic rodents. Hippocampal theta oscillations are crucial for sensorimotor integration, memory consolidation, and network coordination, and depend on synaptic and ionic mechanisms, including the Ih current, mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Lamotrigine (LTG), an HCN channel modulator, influences neuronal excitability and oscillations. Amyloid beta (Aβ) peptide, specifically Aβ_1-42 form plays a key role in AD pathology, promoting hyperexcitability, synaptic dysfunction, and neurodegeneration, particularly in the hippocampus (HPC) and associative cortices. However, only a few electrophysiological studies have examined HPC theta in relation to early cognitive deficits in sAD animal models. Our first goal was to study the temporal progression of theta oscillations impairment following repeated unilateral intracerebroventricular (ICV) Aβ_1-42 infusions in rats at 7, 14, and 21 days, in vivo and in vitro. Second, we assessed whether local LTG administration could restore theta oscillations and long-term potentiation (LTP) in this model. We found that: i) Aβ_1-42 ICV infusions led to significant reductions in theta amplitude and power on days 7 and 14, with a complete loss by day 21; ii) LTG restored LTP and theta rhythms in terms of power and amplitude in HPC obtained from Aβ_1-42-treated animals 14 days post-ICV infusion; iii) histological analysis confirmed neurodegeneration, Tau hyperphosphorylation, astrogliosis, increased number of parvalbimun positive (PV+) interneurons, and GluN2B receptor upregulation in HPC of Aβ_1-42-treated animals 14 days post-ICV infusion. These findings suggest that hippocampal theta disruption may serve as an early biomarker of network dysfunction in sAD, and that LTG-mediated partial restoration of theta and LTP offers a potential early therapeutic strategy.