AlphaCaMKII and NMDA-receptor subunit expression in epileptogenic cortex from human periventricular nodular heterotopia.
OBJECTIVE
Periventricular nodular heterotopia (PNH) is the most common human brain dysgenesis, very frequently characterized by focal drug-resistant epilepsy. To understand the cellular mechanisms underlying its intrinsic hyperexcitability, we investigated the expression of glutamate-receptor subunits and related proteins in four human patients affected by PNH.


METHODS
PNH was diagnosed by means of magnetic resonance imaging. The epileptogenic area was revealed by depth electrode recordings and removed during epilepsy surgery. Sections from the removed cerebral tissue were analyzed by means of immunocytochemistry (ICC), with antibodies directed against N-methyl-d-aspartate (NMDA)-receptor subunits, the alpha subunit of the Ca2+/calmodulin-dependent kinase II (alphaCaMKII), and its active phosphorylated form.


RESULTS
The ICC data demonstrated that the subcortical heterotopic nodules were consistently characterized by lower expression of alphaCaMKII and its activated form. In more pronounced cases (i.e., when the extension of the nodules to the neocortex determined clear layering abnormalities), the heterotopic tissue also was characterized by a decreased expression of NMDA-receptor subunits, which was particularly evident in the dendritic compartment.


CONCLUSIONS
These data suggest the existence of an alteration of alphaCaMKII and the NMDA-receptor complex in the epileptogenic brain tissue of human PNH, which may play a role in the basic mechanisms of hyperexcitability associated with this brain dysgenesis.
Molecular Neuroanatomy Laboratory, Department of Experimental Neurophysiology, C. Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy. battaglia.besta@interbusiness.it
Giorgio
G
Battaglia
Silvia
S
Pagliardini
Arianna
A
Ferrario
Fabrizio
F
Gardoni
Laura
L
Tassi
Veronica
V
Setola
Rita
R
Garbelli
Giorgio
G
LoRusso
Roberto
R
Spreafico
Monica
M
Di Luca
Giuliano
G
Avanzini
D000328:Adult; D001927:Brain Diseases / Q000150:complications*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D002828:Choristoma / Q000150:complications*; D004827:Epilepsy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
D007527:Isoenzymes; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases