Researchers led by Amar Sahay at Massachusetts General Hospital and Harvard Medical School found that restoring a transcriptional regulator in a specific class of inhibitory neurons in adult mice reversed seizures, hippocampal network dysfunction and behavioral deficits associated with a neurodevelopmental disorder (NDD) risk gene, according to a study published August 12 in Nature. The findings suggest that some developmental circuit abnormalities may remain reversible in adulthood.
The researchers used a cell-specific gene-expression screen to identify genes regulating experience-dependent plasticity in parvalbumin (PV) interneurons in the hippocampus. Many of the identified genes overlapped with genetic risk factors for autism spectrum disorder (ASD), epilepsy, schizophrenia and bipolar disorder. The team selected the transcription factor MEIS2 for proof-of-concept experiments testing whether restoring PV interneuron plasticity could reverse established neurological deficits.
MEIS2 was delivered to hippocampal PV interneurons in adult Cntnap2-deficient mice, a model carrying loss of a high-confidence ASD and epilepsy risk gene. Treatment restored multiple measures of PV interneuron function and improved hippocampal sharp-wave ripples, network oscillations associated with memory processing. Spontaneous seizures were observed in 10 of 14 control-treated Cntnap2-deficient mice compared with three of 12 receiving MEIS2, while deficits in social behavior were also improved.
PV interneuron dysfunction has previously been implicated across several NDDs, but the study provides evidence that restoring an underlying plasticity program after development can correct established circuit and behavioral abnormalities. Rather than manipulating a single neurotransmitter or synaptic protein, MEIS2 regulates a broader transcriptional program involved in PV interneuron connectivity, excitability and plasticity. The adult rescue is particularly notable because developmental disruption of these circuits might otherwise be expected to produce persistent abnormalities.