HDAC inhibitors dysregulate neural stem cell activity in the postnatal mouse brain

Area of Science:

• Neuroscience
• Developmental Biology
• Pharmacology

Background:

• The mammalian central nervous system (CNS) expands postnatally, involving neurogenesis and gliogenesis crucial for neural circuit function.
• Pediatric epilepsy often emerges during this developmental period and is treated with valproate/valproic acid (VPA), a histone deacetylase inhibitor (HDACi).
• Specific HDACs play roles in neuronal and glial differentiation, suggesting HDAC inhibition could impact CNS development.

Purpose of the Study:

• To investigate the impact of VPA, a clinical HDAC inhibitor, on postnatal neurogenesis and neural stem cell (NSC) differentiation.
• To determine if VPA directly affects NSC activity and progeny development in specific brain regions.

Main Methods:

• Administered VPA to mice during a critical postnatal week (P7-P14) and used thymidine analogs to track cell production and differentiation.
• Utilized cross-fostering to distinguish direct VPA effects from indirect effects like failure to thrive.
• Employed neurosphere assays with VPA and Trichostatin A (TSA) to assess direct effects on NSC proliferation and differentiation in vitro.

Main Results:

• Short-term VPA treatment significantly reduced NSC progeny production and differentiation in the dentate gyrus (DG), rostral migratory stream (RMS), and olfactory bulb (OB).
• VPA's impact on DG neurogenesis was partly mediated by induced postnatal failure to thrive, but OB interneuron genesis was directly and differentially reduced.
• In vitro, VPA and TSA decreased neurosphere number and size, confirming direct inhibition of NSC activity by HDAC inhibitors.

Conclusions:

• Clinically relevant HDAC inhibitors, including VPA and TSA, can significantly perturb critical windows of postnatal neurogenesis.
• The findings highlight the need for careful consideration of HDAC inhibitor use in developing brains, particularly during sensitive periods.
• This research underscores the potential for therapeutic agents to unintentionally interfere with neurodevelopmental processes.