Mature Hippocampal Neurons Require LIS1 for Synaptic Integrity: Implications for Cognition

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Platelet-activating factor acetylhydrolase 1B1 (LIS1) is crucial for neuronal migration during development.
• LIS1 expression persists in the mature brain, but its adult functions are less understood.
• Previous studies indicated LIS1's role in synaptic formation and turnover in young brains.

Purpose of the Study:

• To investigate the necessity of LIS1 for maintaining hippocampal circuit function in adult mice.
• To elucidate the consequences of LIS1 loss on synaptic function, neuronal connectivity, and cognition in the mature brain.

Main Methods:

• Conditional inactivation of Lis1 in excitatory CA1 pyramidal neurons of juvenile mice.
• Utilized designer receptor exclusively activated by designer drug (DREADD) technology for precise neuronal activity manipulation.
• Combined electrophysiology, hippocampus-selective behavioral testing, and MRI tractography to assess circuit function and connectivity.

Main Results:

• Conditional Lis1 inactivation caused progressive postsynaptic dysfunction within 10 days.
• By postnatal day 60, Lis1 loss led to CA1 disorganization, loss of parvalbumin interneurons, and reduced inhibitory neurotransmission.
• Behavioral and cognitive deficits were observed, alongside a progressive decline in hippocampal efferent pathway connectivity.

Conclusions:

• LIS1 is essential for maintaining synaptic function and plasticity in mature CA1 neurons.
• Postjuvenile LIS1 loss disrupts hippocampal structure, cellular composition, and brain connectivity.
• Cognitive functions dependent on hippocampal circuits are impaired by LIS1 deficiency.