2-1 Signaling Drives Pathological Synaptogenesis, Cell Death and Epileptogenic Circuit Reorganization in a Model of Insult-Induced Cortical Malformation
Lau, Lauren.
2017
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Abstract: Developmental cortical malformations (DCM) are a common cause of
pharmacoresistent epilepsy. DCMs are a group of diverse disorders, associated with varied
seizure phenotypes and co-morbidities, including cognitive impairments and developmental
delays. DCMs can result from genetic mutations, as well as pre- and peri-natal insults.
Hypoxia, viral infection, and traumatic injury are the... read moremost common environmental causes of
DCMs, and are associated with the sub-syndromes polymicrogyria, schizencephaly, and focal
cortical dysplasia Type IIId. To understand how neonatal brain insult leads to cortical
malformation and network dysfunction, we utilized the neonatal freeze lesion (FL) model. A
freezing insult is delivered to the skull on the day of birth, inducing a focal hypoxic
insult. A cortical malformation develops, along with hyperexcitability and spontaneous
seizures. We found here that thrombospondin (TSP) is upregulated following FL. During
normal development, TSP drives excitatory synapse formation. The neuronal receptor for
TSP-mediated synaptogenesis is the calcium channel subunit 2-1, which is also upregulated
following FL. We hypothesize that increased TSP/2-1 signaling may lead to exuberant
excitation in the FL cortex. The drug gabapentin (GBP) blocks 2-1-mediated
synaptogenesis, and in several models, prevents injury-induced hyperexcitability and cell
death. We found that GBP treatment prevented excitatory synaptogenesis, network
hyperexcitability and cell death following FL. GBP has multiple targets, however, and it is
unknown whether its neuroprotective effects are mediated by its actions on 2-1. To
address this, we genetically deleted 2-1 and examined FL-induced pathology using
electrophysiological and anatomical approaches. Deletion of 2-1 reduced FL-driven cell
death, malformation, excitatory synaptogenesis, and network hyperexcitability. Genetic
deletion of 2-1 also eliminated gabapentin's neuroprotective effects and the majority of
its effects on network physiology. GBP did have a mild 2-1-independent effect on
excitatory synaptogenesis. Our studies show that 2-1 activity contributes to FL
pathophysiology and that gabapentin acts at 2-1 to provide neuroprotection and to prevent
injury-induced synaptogenesis and epileptiform network formation. This suggests that
inhibiting 2-1 signaling may have therapeutic promise to reduce cell death and
epileptogenic network reorganization associated with neonatal injury and developmental
cortical malformations.
Thesis (Ph.D.)--Tufts University, 2017.
Submitted to the Dept. of Neuroscience.
Advisor: Chris Dulla.
Committee: Jamie Maguire, Rob Jackson, Yongjie Yang, and Alexander Rotenberg.
Keyword: Neurosciences.read less - ID:
- gt54m060r
- Component ID:
- tufts:23400
- To Cite:
- DCA Citation Guide EndNote
