Age-Dependent Remodeling of Parvalbumin Interneuron-Associated Networks Alters Corticospinal Output in the Motor Cortex

The primary motor cortex (M1) controls voluntary movements through coordinated interactions between excitatory pyramidal neurons and inhibitory parvalbumin-expressing interneurons (PV-INs). Although PV-INs are critical to regulating motor output and motor coordination, their role in age-related motor decline remains unclear. Here, we investigated how aging alters PV-IN-associated regulation of corticospinal tract (CST) output in mice. Aged mice (14–24 months) exhibited selective motor impairments, including deficits in balance and hindlimb-supported performance, while general locomotor activity remained largely preserved. We combined optogenetics, ex vivo electrophysiology, retrograde tracing, and in vivo electromyographic (EMG) recordings. In aged M1 slices, optogenetic stimulation of the PV-IN-targeted network produced small extracellular-like voltage deflections recorded with a loose-apposed, non-sealed pipette configuration. These responses persisted during GABAA receptor blockade but were abolished by DNQX and APV, indicating engagement of an ionotropic glutamate receptor-dependent network mechanism. Whole-cell recordings obtained in separate experiments demonstrated that conventional inhibitory PV-IN-to-pyramidal transmission remained detectable during repetitive stimulation. In vivo, PV-IN activation increased M1-evoked hindlimb EMG responses in aged mice but had little effect in young animals. Together, these findings identify an age-dependent reorganization of PV-IN-associated motor-cortical network function that alters the recruitment of glutamatergic mechanisms and corticospinal motor output. The present data do not establish the precise synaptic topology of this network response or whether the reorganization is compensatory or maladaptive.