SHANK2 affects neuronal hyperexcitability through glutaminergic synaptic signaling in early Alzheimer's disease
Background: Neuronal hyperexcitability is an important feature of early Alzheimer's disease (AD); however, its mechanism remains unclear. This study investigates the role and mechanism of SH3 and multiple ankyrin repeat domains 2 (SHANK2) in neuronal hyperexcitability in early-stage AD.Methods: C57BL/6J and 5xFAD mice aged 3 months were used to establish a mouse pentatetrazole (PTZ)-induced chronic epilepsy model. Video monitoring and local field potentials in the hippocampus were used to monitor epileptic behavior. Neuronal excitability was recorded using a patch clamp. Proteomics, transcriptomics, and bioinformatics analyses screened key targets of AD neuron over-excitation. Adeno-associated virus or lentivirus vectors were injected into the hippocampus to knock down or over-express SHANK2. The Morris water maze and Y maze were used to assess cognitive function.Results: 5xFAD mice were more susceptible to epilepsy than C57BL/6J mice. Action potential frequency increased, miniature excitatory postsynaptic current amplitude increased, frequency decreased, and PPR increased in the 5xFAD group, indicating neuronal hyperexcitability in the early AD period. SHANK2 expression was significantly reduced in the 5xFAD+PTZ group. SHANK2 was identified as the key target of early AD neuronal overexcitation, while the glutaminergic synaptic signaling pathway was the key signaling pathway. Hippocampal Shank2 knockdown and overexpression significantly reduced and enhanced cognitive dysfunction and epilepsy susceptibility and severity in 5xFAD mice, respectively. Additionally, SHANK2 affected AMPAR- and NMDAR-mediated excitatory postsynaptic currents. Conclusions: Shank2 affects neuronal hyperexcitability in the early stages of AD through glutamatergic synaptic signals, thus providing new targets and strategies for the early clinical treatment of AD.