Expression patterns of synaptic vesicle protein 2A in focal cortical dysplasia and TSC-cortical tubers * 1 Sjoukje T. Toering, y 1 Karin Boer, *y 1 Marjolein de Groot, yDirk Troost, *Jan J. Heimans, zWim G. M. Spliet, xPeter C. van Rijen, {Floor E. Jansen, **yyJan A. Gorter, *Jaap C. Reijneveld, and y**Eleonora Aronica *Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands; yDepartment of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; zDepartment of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands; xDepartment of Neurosurgery, University Medical Center Utrecht, Utrecht, The Netherlands; {Department of Child Neurology/ Rudolf Magnus Institute for Neurosciences, University Medical Center Utrecht, Utrecht, The Netherlands; **Stichting Epilepsie Instellingen Nederland, Heemstede, The Netherlands; and yyCenter for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands SUMMARY Purpose: Synaptic vesicle protein 2A (SV2A), the binding site for the antiepileptic drug (AED) leveti- racetam, has been shown to be involved in the con- trol of neuronal excitability. The aim of the study was to define the expression and cell-specific dis- tribution of SV2A in developmental focal lesions associated with medically intractable epilepsy. Methods: SV2A immunocytochemistry and Wes- tern blotting was performed in focal cortical dys- plasia (FCD type IIB) and cortical tubers from patients with tuberous sclerosis complex (TSC). Results: Autopsy and surgical control neocortical specimens were characterized by strong SV2A immunoreactivity throughout all cortical layers, with punctate labeling around the somata and dendrites of neurons. In FCD and cortical tuber specimens less intense, SV2A immunoreactivity was observed in the neuropil. The reduction in expression was confirmed by Western blot analy- sis. In both FCD and tuber specimens, clusters of punctate labeling were detected along cell borders and processes (perisomatic synapses) of dysplastic neuronal cells localized in both gray and white matter. The large majority of balloon cells in FCD, or giant cells in tubers, did not show punctate labeling around their somata. SV2A immuno- reactivity was observed occasionally within the neuronal perikarya. Conclusions: The pattern of SV2A immunoreac- tivity with reduced neuropil expression and altered cellular and subcellular distribution sug- gests a possible contribution of SV2A to the epi- leptogenicity of these malformations of cortical development. Knowledge of the expression pat- tern of SV2A in epilepsy-associated pathologies may be valuable for the evaluation of the effective- ness of AEDs targeting this protein. KEY WORDS: Synaptic vesicle protein, Human, Cortex, Cortical dysplasia, Tuberous sclerosis complex, Epilepsy. Malformations of cortical development (MCDs) repre- sent an increasingly recognized cause of intractable pedi- atric epilepsy (Thom, 2004; Wong, 2008). A subset of MCD, represented by focal lesions with abnormal glio- neuronal proliferation, shares common histologic and molecular features, suggesting common pathogenic and epileptogenic mechanisms (Barkovich et al., 2005; Wong, 2008). The resistance to pharmacologic treatment with a broad range of antiepileptic drugs (AEDs) is char- acteristic of these developmental lesions and increases the clinical significance and social impact of this subset of pediatric epilepsies (Mathern et al., 1999; Aronica et al., 2001; Wong, 2008). An unresolved question concern- ing epileptogenesis in focal epilepsy is whether seizures Accepted October 9, 2008; Early View publication February 12, 2009. Address correspondence to Dr. E. Aronica, Department of (Neuro)Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: e.aronica@amc.uva.nl 1 Authors contributed equally to the present work. Wiley Periodicals, Inc. ª 2009 International League Against Epilepsy Epilepsia, 50(6):1409–1418, 2009 doi: 10.1111/j.1528-1167.2008.01955.x FULL-LENGTH ORIGINAL RESEARCH 1409