Alterations in mRNA expression of systems that regulate neurotransmitter synaptic content in seizure-naive genetically epilepsy-prone rat (GEPR): transporter proteins and rate-limiting synthesizing enzymes for norepinephrine, dopamine and serotonin.

Abstract Two models of genetically epilepsy-prone rat (GEPR) exist, the GEPR-3 and GEPR-9. GEPR-3 and GEPR-9 share a deficiency in presynaptic norepinephrine (NE) and serotonin (5HT) content in specific regions of the central nervous system (CNS). The presynaptic content of dopamine (DA) does not appear to be altered in either adult GEPR strain compared to Sprague–Dawley (SD) rats, the strain from which the GEPR was derived. Presynaptic content of monoamine neurotransmitters, such as NE, 5HT and DA, are maintained by several regulatory proteins which include: synthesis, re-uptake, release, degradation and vesicular transport. To further characterize the monoamine deficiency observed in the GEPR, the mRNA level of the rate limiting enzymes for the synthesis of NE, 5HT and DA and each of the neurotransporter proteins were measured in seizure-naive GEPR-3, GEPR-9 and SD rats. In the locus coeruleus (LC), the major noradrenergic locus, tyrosine hydroxylase (TH) mRNA level was significantly reduced only in GEPR-9 animals compared to SD rats and GEPR-3; while NE transporter (NET) mRNA was significantly elevated in GEPR-3 compared to SD rats and GEPR-9. TH and DA transporter (DAT) mRNA was measured in the dopaminergic neurons of the substantia nigra pars compacta (SNpc), ventral tegmental area (VTA) and zona incerta (ZI). DAT mRNA level was significantly reduced in all dopaminergic neurons in the GEPR-3 compared to SD rats and GEPR-9, while TH mRNA level was significantly elevated in the SNpc/VTA equally in GEPR-3 and GEPR-9 compared to SD rats. In the ZI, TH mRNA level was significantly reduced in GEPR-3 compared to SD rats and GEPR-9. In the dorsal raphe (DR), a major serotonergic locus, tryptophan hydroxylase (TRH) mRNA level was not significantly different from SD in either strain of GEPR; however, 5HT transporter (SERT) mRNA level was significantly reduced in GEPR-9 in the dorsal and lateral regions of the DR compared to SD rats and GEPR-3. These data indicate that two of the regulatory systems that maintain NE, 5HT and DA content are altered in a differential manner in seizure-naive GEPR-3 compared to seizure-naive GEPR-9, with GEPR-3 showing more alterations in dopaminergic neurons. It is uncertain at the present time how these alterations in mRNA level relate to the enhanced seizure susceptibility of these animals. It was apparent that a straightforward correlation between neurotransmitter loss to transcriptional changes in synthesizing enzymes mRNA or to re-uptake protein mRNA was not observed in noradrenergic and serotonergic neurons. Therefore, the decrease in presynaptic NE and 5HT tissue content in these animals may be due to posttranscriptional modification. In contrast, presynaptic DA tissue content which was unaltered in both strains of GEPR, shows an alteration in TH and DAT mRNA level compared to SD rats in all dopaminergic neurons examined. This indicates a possible involvement of DA in regulating the seizure susceptibility of these animals.