Spatiotemporal patterns of gene expression changes in the mouse dentate gyrus following entorhinal denervation

The central nervous system responds to acute injury with plastic remodeling of its network. However, the temporal and structural dynamics of this response in the denervated dentate gyrus remain poorly understood. Therefore, we examined the transcriptional programs activated after perforant path transection, focusing on the outer molecular layer (OML) and the granule cell layer (GCL).

Perforant path transections were performed, and tissue from the denervated OML and GCL was selectively isolated using laser microdissection at 1, 3, 7, 14, and 28 days post-lesion. Whole-genome expression analysis was performed to identify and characterize global transcriptome changes across time and layers.

Denervation induced reactive astrogliosis and microgliosis primarily in the OML. Overall enrichment statistics from two complementary approaches highlighted early downregulations of neuroactive ligands, later downregulation of (mainly glutamatergic) neurotransmission factors, and late downregulations of respiratory factors, alongside early upregulations of debris degradation factors, subsequent upregulation of glial and inflammatory factors, and late upregulation of ribosomal translation. Entorhinal afferent loss was reflected by reductions of the axon repellent Sema3e (to 60% in OML), with sustained depletions of the reelin repressor Adamts3 (14% in OML, 33% in GCL) and its presumptive effector Ptpn3 (30% in OML), as well as delayed induction of the SEMA3E/reelin coreceptor Nrp1 (3-fold in OML, 7-fold in GCL). Secondary reductions in the GCL occurred for the CREB repressor Rgs13, Ntng1, and Epha5-Epha6-Epha7. Deficits were found in the OML for glutamatergic signaling factors (Neto1, Cnih2, Dlg2, Gria1, Grm7-Grm8-Grm3, Homer2, Trim32), in the GCL for GABAergic and glycinergic receptors (Gabra2-Gabra1, Gabrb2, Glra2), and overall for neuronal differentiation markers (Calb1, Pvalb, Gad1, Lrrc7, Ano3, Bdnf, Egfr, Igf2r, Nrep, Basp1, Scn1a) and synaptic adhesion mediators (Lingo2, Lrrtm1-Lrrtm3, Adam11-Adam23, Cadm2, Pcdhb16, Flrt3). Presumed compensatory upregulation efforts included postsynaptic and dendritic membrane remodeling by vesicle and actin regulators (Lyn, Gabarap, Cyfip1, Arf4, Arl4c, Rab8b, Cdk5rap2, Tmsb4x) in the OML, versus neurotrophic coreceptors Sorcs3-Sorcs2, axonal Smn1, and the neural progenitor modulator Nup210l in the GCL.

These findings identify coordinated and temporally structured transcriptomic programs that reflect injury-induced remodeling in the dentate gyrus and highlight novel molecular mediators of synaptic reorganization, neuroinflammation, metabolic adaptation, and compensatory plasticity following entorhinal denervation.