2-1 Signaling Drives Pathological Synaptogenesis, Cell Death and Epileptogenic Circuit Reorganization in a Model of Insult-Induced Cortical Malformation
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 th... read moree most 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
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