Maladaptive cortical hyperactivity upon recovery from experimental autoimmune encephalomyelitis.

Area of Science:

• Neuroscience
• Immunology
• Neurodegeneration

Background:

• Multiple sclerosis (MS) patients often show neuropsychological symptoms early, despite immune attacks primarily targeting white matter and the spinal cord.
• The reasons for early neurodegeneration in MS and its prominence in later stages remain unclear.

Purpose of the Study:

• To investigate the activity of cortical microcircuits in early multiple sclerosis.
• To explore the link between immune response, neuronal activity, and neurodegeneration in MS.

Main Methods:

• Utilized spiking-specific two-photon calcium imaging in vivo in proteolipid protein-immunized relapsing-remitting SJL/J mice.
• Assessed cortical neuronal activity, caspase-3 expression, and TNFα levels.
• Administered intraventricular infliximab to block TNFα and measured its effects on neuronal activity and behavior.

Main Results:

• Identified hyperactive cortical neurons during remission, independent of direct immune damage.
• Observed increased caspase-3 expression correlating with high neuronal activity.
• Found increased cortical TNFα expression in excitatory neurons during remission.
• Infliximab treatment normalized neuronal network activity, restored AMPA receptor function, and alleviated anxiety.

Conclusions:

• Early MS involves cortical network dysregulation and hyperactivity, potentially as a compensatory mechanism via synaptic plasticity.
• This suggests a connection between immune attack, synaptic plasticity, and the onset of neurodegeneration in MS.
• Targeting TNFα may offer therapeutic potential for early neuropsychological symptoms in MS.