Autism-Epilepsy Phenotype in Mice with Developmental Interneuron Specific Deletion of Neuropilin-2
Abstract number :
1.022
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2023
Submission ID :
444
Source :
www.aesnet.org
Presentation date :
12/2/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Deepak Subramanian, PhD – University of California - Riverside
Andrew Huang, BS – Division of Biomedical Sciences – University of California - Riverside; Carol Eisenberg, PhD – Department of Biological Sciences – Rutgers University; Jiyeon Baek, BS – Department of Biological Sciences – Rutgers University; Michael Shiflett, PhD – Department of Psychology – Rutgers University; Tracy Tran, PhD – Department of Biological Sciences – Rutgers University; Viji Santhakumar, MD, PhD – Molecular, Cell and Systems Biology – University of California - Riverside
Rationale:
Early developmental perturbations in circuit formation have been proposed to underlie autism spectrum disorders (ASDs) and epilepsy. We previously demonstrated that mice with global constitutive knockout (KO) of Neuropilin 2 (Nrp2), a secreted semaphorin receptor essential for neural circuit formation and synapse maintenance, exhibit abnormal social interactions and increased seizure susceptibility. Developmentally, Nrp2 is expressed in inhibitory neuron precursors in the median ganglionic eminence and regulates interneuron migration to the pallium, including the hippocampus. Here we examined the specific effect of developmental deletion of Nrp2 in inhibitory neuron progenitors on hippocampal circuit function.
Methods:
Pregnant female Nrp2f/f::Nkx2.1-CreERT2 and control mice were fed with tamoxifen at E12.5-13.5 to selectively delete Nrp2 in inhibitory neuron precursors during the period of migration generating interneuron conditional knockout (iCKO) mice. Hippocampal interneuron subtypes were quantified in adult control/ iCKO mice using immunostaining. Whole-cell patch clamp recordings from CA1 pyramidal neurons were used to examine intrinsic physiology, spontaneous and miniature postsynaptic currents (sEPSC/sIPSC and mEPSC/mIPSC respectively). Seizure susceptibility was evaluated as the latency to convulsive seizures following kainic acid injection (20mg/kg; i.p.). Adult control/ iCKO mice were assessed for social preference in a 3-chambered arena and goal-directed learning in an instrumental conditioning task.
Results:
Consistent with the role for Nrp2 in interneuron migration, iCKO mice showed significant reduction in parvalbumin, neuropeptide Y, and somatostatin positive neurons in CA1. Although CA1 neurons from WT and iCKO mice did not differ in intrinsic passive and active membrane properties, sIPSC and mIPSC frequency was reduced in iCKO mice (Table 1). Interestingly, sEPSC but not mEPSC frequency was reduced in CA1 neurons from iCKO animals. At the functional level, the circuit changes in excitation and inhibition contributed to a reduction in latency to kainic acid evoked seizures (control: 27.7±3.3 min, iCKO: 4.8±1.9 min, n = 5 and 3 mice, p< 0.01) in iCKO mice. Importantly, iCKO mice exhibited reduction in both social preference and goal-directed learning compared to littermate controls.
Basic Mechanisms