MULTISCALE ELECTROPHYSIOLOGY REVEALS NEUROPLASTIN AND PMCA CONTROL OF CORTICAL EXCITABILITY

Learning and memory recall are encoded within specific neuronal circuits; however, the molecular mechanisms supporting these processes remain largely unknown. Neuroplastin (Np), a synaptic glycoprotein of the immunoglobulin superfamily, plays a key role in synaptic plasticity and memory. Np binds and stabilizes the plasma membrane Ca²⁺ ATPase (PMCA1–4), an ultrafast ATP-driven calcium extrusion pump. In the absence of Np, PMCA levels are reduced, leading to delayed extrusion and elevated intracellular calcium, which may compromise neuronal function.
Previous studies showed that Np deletion after successful training on a light-cued associative memory task leads to retrograde amnesia in mice. Interestingly, memory recall is not impaired following Np elimination in excitatory neurons, suggesting a critical role of Np in GABAergic interneuron function. These interneurons modulate and synchronize cortical circuits and may be particularly sensitive to intracellular calcium dysregulation.
To investigate how Np and PMCA contribute to cortical network dynamics, extracellular electrophysiological recordings were performed in cortical neuronal cultures treated with a PMCA inhibitor and in acute coronal slices of the primary visual cortex (V1) from Nptn⁻/⁻ and Nptn⁺/⁺ mice. PMCA inhibition with Carboxyeosin (10 μM) induced a global increase in firing rate in cultured networks. High-density MEA recordings in V1 slices revealed increased firing rates in putative pyramidal neurons from Nptn⁻/⁻ mice, particularly in layers 2/3 and 6, while putative interneurons showed reduced firing rates, mainly in layers 4 and 6.
Together, these findings highlight cell–type–specific and local circuit contributions of Np to cortical excitability in V1.