Chronic Activation of Gp1 mGluRs Leads to Distinct Refinement of Neural Network Activity through Non-Canonical p53 and Akt Signaling

Abstract

Group 1 metabotropic glutamate receptors (Gp1 mGluRs), including mGluR1 and mGluR5, are critical regulators for neuronal and synaptic plasticity. Dysregulated Gp1 mGluR signaling is observed with various neurologic disorders, including Alzheimer’s disease, Parkinson’s disease, epilepsy, and autism spectrum disorders (ASDs). It is well established that acute activation of Gp1 mGluRs leads to elevation of neuronal intrinsic excitability and long-term synaptic depression. However, it remains unknown how chronic activation of Gp1 mGluRs can affect neural activity and what molecular mechanisms might be involved. In the current study, we employed a multielectrode array (MEA) recording system to evaluate neural network activity of primary mouse cortical neuron cultures. We demonstrated that chronic activation of Gp1 mGluRs leads to elevation of spontaneous spike frequency while burst activity and cross-electrode synchronization are maintained at the baseline. We further showed that these neural network properties are achieved through proteasomal degradation of Akt that is dependent on the tumor suppressor p53. Genetically knocking down p53 disrupts the elevation of spontaneous spike frequency and alters the burst activity and cross-electrode synchronization following chronic activation of Gp1 mGluRs. Importantly, these deficits can be restored by pharmacologically inhibiting Akt to mimic inactivation of Akt mediated by p53. Together, our findings reveal the effects of chronic activation of Gp1 mGluRs on neural network activity and identify a unique signaling pathway involving p53 and Akt for these effects. Our data can provide insights into constitutively active Gp1 mGluR signaling observed in many neurologic and psychiatric disorders.