Altered expression of neurotransmitter-receptor subunit and uptake site mRNAs in hemimegalencephaly

Purpose: Hemimegalencephaly (HMEG) is characterized by unilateral hemispheric enlargement and severe cytoarchitectural abnormalities that are highly associated with intractable epilepsy. No studies have defined alterations in neurotransmitter-receptor subunit gene expression in HMEG. We hypothesize that a differential expression of excitatory amino acid and gamma-aminobutyric acid (GABA)(A) -receptor subunit messenger RNAs (mRNAs) exists in HMEG. Methods: The expression of mRNAs encoding 20 neurotransmitter-receptor subunits, synthetic enzymes. and uptake sites as well as select additional candidate genes was defined in HMEG samples (n = 8) compared with homotopic control cortex specimens by using targeted complementary DNA (cDNA) arrays. Expression of GLT-1 (a glial glutamate transporter), EAAC-1 (neuronal glutamate transporter), and NMDA2B was corroborated by immunohistochemical, Western, and ligand-binding assays. Results: Differential expression of 11 neurotransmitter-related mRNAs was demonstrated in HMEG compared with control cortex. For example, expression GLT-1 and GluR6 mRNAs was enhanced, whereas diminished expression of the neuronal glutamate transporter EAAC-1, GABA(A)alpha2, GABA(A)gamma2, GABA(A)gamma3. NMDA2B, GluR1, GluR2, GluR4, and GluR5 subunits occurred. Reduced NMDA2B subunit mRNA expression in HMEG was confirmed by receptor ligand-binding assays by using the NMDA2B-receptor antagonist ifenprodil. which revealed barely detectable levels of NMDA2B binding compared with that in control cortex. Conclusions: Selective alterations occur in distinct neurotransmitter-receptor and -uptake sites in HMEG. Differential expression of neurotransmitter-receptor and -uptake sites in HMEG may contribute to epileptogenesis in HMEG.