Dendritic Beading in Neonatal Brain Circuits Causes Aberrant Signal Transmission and Impaired Synaptic Plasticity
Abstract number :
3.058
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2024
Submission ID :
120
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Pratyush Suryavanshi, PhD – University of Iowa
Satya Murthy Tadinada, PhD – University of Iowa
Samuel Baule, PhD – University of Iowa
Naisha Jhaveri-Cruz, PhD – University of Iowa
Ted Abel, PhD – University of Iowa
Joseph Glykys, MD, PhD – University of Iowa
Rationale: Intellectual disability and cognitive impairment are frequent in epilepsy patients, including in infants who experienced severe seizures as neonates. Yet, the underlying mechanisms causing cognitive impairment remain elusive. Human tissue and animal models of focal intractable epilepsy show a marked loss of dendritic spines and varicose swellings (beading) of dendrites. As dendrites integrate multiple synaptic inputs through dendritic spines, we studied the role of dendritic beading during neonatal seizures in synaptic signal processing and hippocampal plasticity.
Methods: We used two-photon laser scanning microscopy to image changes in dendritic morphology (Thy1-H-YFP) and dendritic Ca2+ activity (Thy1-GCaMP6s) in mouse neonatal (neocortical and hippocampal) acute brain slices (P8-12) before, during and after the perfusion of 30 µM NMDA (10 min). Neocortical and hippocampal field potentials were measured using extracellular electrophysiology.
Results: Dendritic beads were reliably induced by NMDA in basal and oblique branches/tufts of the apical dendrites and showed a uniform spatial distribution away from neuronal soma. However, beading was consistently absent in primary apical dendrites. Long-term dendritic beading was reversible in hypertonic conditions. Dendritic beads exhibited persistent elevation of intracellular Ca2+. Dendrites with varicose beads showed either attenuated or completely abolished synaptically-evoked Ca2+ transients. Finally, we evaluated the effect of dendritic beading on hippocampal synaptic plasticity. After NMDA treatment, hippocampal (CA3 to CA1) evoked field potentials were temporarily suppressed, with only ~50% of hippocampal slices showing recovery after 90 mins. After tetanic stimulation, the recovered NMDA-treated slices showed a reduction in both post-tetanic and long-term potentiation compared to controls.
Conclusions: Our findings show that dendritic beading in neonatal slices leads to deficits in hippocampal short and long-term synaptic plasticity, implicating dendritic dysfunction in cognitive deficits. These findings could be translated to other disorders of neuronal hyperexcitability associated with cognitive defects.
Funding: JG: NIH/NINDS R01NS115800, Iowa Neuroscience Institute. PS: AES postdoctoral fellowship (#1066027). TA: Roy J. Carver Chair in Neuroscience, Carver College of Medicine
Basic Mechanisms