SYVN1, an ERAD E3 Ubiquitin Ligase, Is Involved in GABA(A)α1 Degradation Associated with Methamphetamine-Induced Conditioned Place Preference

Abuse of methamphetamine (METH), a powerful addictive amphetamine-type stimulants (ATS), is becoming a global public health problem. The gamma-aminobutyric acid (GABA)ergic system plays a critical role in METH use disorders. By using rat METH conditioned place preference (CPP) model, we previously demonstrated that METH-associated rewarding memory formation was associated with the reduction of GABA(A)α1 expression in the dorsal straitum (Dstr), however, the underlying mechanism was unclear. In the present study, we found that METH-induced CPP formation was accompanied by a significant increase in the expression of Synovial apoptosis inhibitor 1 (SYVN1), an endoplasmic reticulum (ER)-associated degradation (ERAD) E3 ubiquitin ligase, in the Dstr. The siRNA knockdown of SYVN1 significantly increased GABA(A)α1 protein levels in both primary cultured neurons and rodent Dstr. Inhibition of proteasomal activity by MG132 and Lactacystin significantly increased GABA(A)α1 protein levels. We further found that SYVN1 knockdown increased GABA(A)α1 in the intra-ER, but not in the extra-ER. Accordingly, endoplasmic reticulum stress (ERS)-associated Glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) increased. Thus, this study revealed that SYVN1, as the ERAD E3 ubiquitin ligase, was associated with Dstr GABA(A)α1 degradation induced by METH conditioned pairing.