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Dlx1 and Dlx2 Promote Interneuron GABA Synthesis, Synaptogenesis, and Dendritogenesis
Ramon Pla1, Amelia Stanco1, MacKenzie A Howard2
1Department of Psychiatry, Neuroscience Program and the Nina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco, San Francisco, CA, USA.
Abstract:
The postnatal functions of the Dlx1&2 transcription factors in cortical interneurons (CINs) are unknown. Here, using conditional Dlx1, Dlx2, and Dlx1&2 knockouts (CKOs), we defined their roles in specific CINs. The CKOs had dendritic, synaptic, and survival defects, affecting even PV+ CINs. We provide evidence that DLX2 directly drives Gad1, Gad2, and Vgat expression, and show that mutants had reduced mIPSC amplitude. In addition, the mutants formed fewer GABAergic synapses on excitatory neurons and had reduced mIPSC frequency. Furthermore, Dlx1/2 CKO had hypoplastic dendrites, fewer excitatory synapses, and reduced excitatory input. We provide evidence that some of these phenotypes were due to reduced expression of GRIN2B (a subunit of the NMDA receptor), a high confidence Autism gene. Thus, Dlx1&2 coordinate key components of CIN postnatal development by promoting their excitability, inhibitory output, and survival.
Insights
Dlx1 and Dlx2 transcription factors are crucial for the postnatal development of cortical interneurons (CINs). These factors regulate neuronal excitability, survival, and the formation of both inhibitory and excitatory synapses.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- The postnatal roles of Dlx1 and Dlx2 transcription factors in cortical interneurons (CINs) remain largely uncharacterized.
- Cortical interneurons are essential for regulating brain activity and are implicated in various neurological disorders.
Purpose of the Study:
- To elucidate the specific postnatal functions of Dlx1 and Dlx2 transcription factors in different subtypes of CINs.
- To investigate the molecular mechanisms by which Dlx1 and Dlx2 influence CIN development and function.
Main Methods:
- Conditional knockout mouse models were generated for Dlx1, Dlx2, and combined Dlx1&2.
- Phenotypic analyses included assessment of dendritic morphology, synaptic function (mIPSC amplitude and frequency), and neuronal survival.
- Gene expression analysis was performed to identify direct targets of DLX2, including Gad1, Gad2, Vgat, and GRIN2B.
Main Results:
- Conditional Dlx1&2 knockouts exhibited significant defects in dendrite development, synaptic function, and neuronal survival, impacting even Parvalbumin-positive (PV+) CINs.
- DLX2 was identified as a direct transcriptional activator of Gad1, Gad2, and Vgat, leading to reduced inhibitory neurotransmission (mIPSC amplitude) in mutants.
- Mutant mice displayed reduced GABAergic synapse formation on excitatory neurons and decreased mIPSC frequency, alongside hypoplastic dendrites and fewer excitatory synapses.
- Reduced expression of GRIN2B, a high-confidence autism gene, was observed in Dlx1/2 mutants, contributing to altered excitatory input.
Conclusions:
- Dlx1 and Dlx2 transcription factors are essential coordinators of postnatal CIN development.
- These factors promote CIN excitability, enhance inhibitory output, and ensure neuronal survival through the regulation of key synaptic and survival genes.
- The findings highlight the critical role of Dlx1&2 in establishing functional neural circuits and provide insights into potential mechanisms underlying neurodevelopmental disorders.