Communication defects with astroglia contribute to early impairments in the motor cortex plasticity of SOD1G93A mice

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, involving the selective degeneration of cortical upper synapses in the primary motor cortex (M1). Excitotoxicity in ALS occurs due to an imbalance between excitation and inhibition, closely linked to the loss/gain of astrocytic function. Using the ALS SOD1G93A mice, we investigated the astrocytic contribution for the electrophysiological alterations observed in the M1 of SOD1G93A mice, throughout disease progression. Results showed that astrocytes are involved in synaptic dysfunction observed in presymptomatic SOD1G93A mice, since astrocytic glutamate transport currents are diminished and pharmacological inhibition of astrocytes only impaired long-term potentiation and basal transmission in wild-type mice. Proteomic analysis revealed major differences in neuronal transmission, metabolism, and immune system in upper synapses, confirming early communication deficits between neurons and astroglia. These results provide valuable insights into the early impact of upper synapses in ALS and the lack of supportive functions of cortical astrocytes, highlighting the possibility of manipulating astrocytes to improve synaptic function. [Display omitted] •Presymptomatic SOD1G93A mice show an impaired synaptic plasticity and transmission, in the primary motor cortex (M1).•Hypoexcitability of M1 neurons in presymptomatic SOD1G93A mice progresses to hyperexcitability in the symptomatic phase.•Astrocytic glutamate transporter currents are diminished in SOD1G93A mice, negatively influencing M1 synaptic plasticity.•Proteomic analysis of M1 synaptosomes reveals excessive glutamatergic neurotransmission and reactive immune response.•This work highlights the early deficits in neuronal-glial communication and its functional impact on plasticity.