The Wnt5a-PKCδ-GluA1 axis controls synapse-specific plasticity in HIV-1 gp120-induced pain pathogenesis

Imbalance of excitatory and inhibitory neuronal activity (E/I imbalance) plays a critical role in pain pathogenesis. Recent studies have identified a novel form of E/I imbalance in the spinal dorsal horn (SDH) of animal models of HIV-associated pain, manifesting as increased spontaneous excitatory postsynaptic current (sEPSC) frequency in excitatory neurons alongside decreased sEPSC frequency in inhibitory neurons and hence termed neural circuitry polarization (NCP). However, how the opposite forms of synaptic plasticity in NCP is coordinated in the pain neural circuit is unclear. Here, we show that in the SDH of a mouse model of HIV-associated pain, potentiation of excitatory synapses on excitatory neurons (ESE) and depression of excitatory synapses on inhibitory neurons (ESI) employ distinct mechanisms to support their expression. We found the increase of sEPSC frequency in excitatory neurons induced by HIV1 gp120 was mediated by a postsynaptic mechanism, whereas decrease of sEPSC frequency in inhibitory neurons by a presynaptic mechanism. Our studies showed that pharmacological inhibition of calcium-permeable AMPA (CP-AMPA) receptors selectively attenuated potentiation of ESE without significantly affecting ESI depression. We also observed that GluA1 was upregulated in excitatory but not inhibitory neurons, indicating selective CP-AMPA receptor formation in excitatory neurons. Furthermore, we identified a new pain-related signaling pathway in ESE: Wnt5a-PKCδ-GluA1. We elucidated that the GluA1 upregulation and ESE potentiation were controlled by neuronal Wnt5a signaling via protein kinase C delta (PKCδ). Our findings reveal that ESE and ESI in the SDH of HIV pain models use distinct synaptic and molecular mechanisms to support their expression in NCP, demonstrating specialized regulatory pathways for the plasticity of excitatory synapses targeting different neuron types during the pain pathogenesis.