Nature study identifies PV neuron plasticity mechanism across four neurodevelopmental disorders
This digest was compiled by AI from multiple sources — links to the originals are below.
A Nature study identifies experience-dependent plasticity of parvalbumin-expressing inhibitory neurons in the hippocampal CA3/CA2 circuit as a convergent mechanism for neurodevelopmental disorder risk genes. Targeted upregulation of the homeobox gene Meis2 in adult mice restored this plasticity, improved cognition and suppressed seizures. The study demonstrates that developmental deficits in circuitry, network excitability and cognition can be reversed in adulthood.
PV Neuron Plasticity in NDDs
The study used an input-specific translatome screen to identify regulators of experience-dependent plasticity genes in CA3/CA2 of adult mouse hippocampus. A substantial proportion of upregulated candidate genes showed haploinsufficiency in autism spectrum disorder, epilepsies, bipolar disorder and schizophrenia. The authors interpret this as evidence of impaired experience-dependent PV IN plasticity in neurodevelopmental disorders. The mechanism centers on fast-spiking parvalbumin-expressing inhibitory neurons that control pyramidal neuron activity through mossy fibre-dependent feedforward inhibition.
Meis2 Restoration in Adult Mice
In proof-of-concept experiments, targeted upregulation of the homeobox gene Meis2 in CA3/CA2 PV INs of an NDD risk mouse model in adulthood restored experience-dependent PV IN plasticity. Meis2 was one candidate experience-dependent plasticity gene identified by the screen. Ensemble and sharp-wave ripple properties improved, and cognition was enhanced while seizures were suppressed. The experiments demonstrate that developmental deficits in circuitry, network excitability and cognition can be reversed in adulthood.
What's Next
It remains to be seen whether other candidate XPGs identified by the screen will produce similar restoration when upregulated. It is also unclear whether the adult mouse findings will translate to human patients with neurodevelopmental disorders.
1 source
Nature study identifies PV neuron plasticity mechanism across four neurodevelopmental disorders
