Abstract
Cocaine exposure during gestation causes protracted neurobehavioral changes consistent with a compromised glutamatergic system. Although cocaine profoundly disrupts glutamatergic neurotransmission and in utero cocaine exposure negatively affects metabotropic glutamate receptor-type 1 (mGluR1) activity, the effect of prenatal cocaine exposure on mGluR1 signaling and the underlying mechanism responsible for the prenatal cocaine effect remain elusive. Using brains of the 21-day-old (P21) prenatal cocaine-exposed rats, we show that prenatal cocaine exposure uncouples mGluR1s from their associated synaptic anchoring protein, Homer1 and signal transducer, Gq/11 proteins leading to markedly reduced mGluR1-mediated phosphoinositide hydrolysis in frontal cortex (FCX) and hippocampus. This prenatal cocaine-induced effect is the result of a sustained protein kinase C (PKC)-mediated phosphorylation of mGluR1 on the serine residues. In support, phosphatase treatment of prenatal cocaine-exposed tissues restores whereas PKC-mediated phosphorylation of saline-treated synaptic membrane attenuates mGluR1 coupling to both Gq/11 and Homer1. Expression of mGluR1, Homer1 or Gα proteins was not altered by prenatal cocaine exposure. Collectively, these data indicate that prenatal cocaine exposure triggers PKC-mediated hyper-phosphorylation of the mGluR1 leading to uncoupling of mGluR1 from its signaling components. Hence, blockade of excessive PKC activation may alleviate abnormalities in mGluR1 signaling and restores mGluR1-regulated brain functions in prenatal cocaine-exposed brains.
Highlights
Cocaine usage during pregnancy causes protracted neurological and behavioral abnormalities [1,2,3]
MGluR1 - Gq/11 complex is associated with scaffolding protein Homer1 but not Homer2 as both Gaq/11 and Homer1 were detected in anti-metabotropic glutamate receptor-type 1 (mGluR1) immunoprecipitate in both brain regions (Fig. 1B)
The effect of prenatal cocaine exposure on the association of mGluR1 with Gq/11 and Homer1 was subsequently determined by the level of Gaq/11 and Homer1 co-immunoprecipitated with mGluR1
Summary
Cocaine usage during pregnancy causes protracted neurological and behavioral abnormalities [1,2,3]. Prenatal cocaine exposure alters glutamatergic function in various brain regions [4,5,6], the effect of gestational cocaine exposure on metabotropic glutamate receptor (mGluR) is not well understood. Prenatal cocaine exposure was shown to directly disrupt mGluR1 function resulting in delays in postnatal synaptic maturation [7]. The mGluRs are members of the G-protein coupled receptor (GPCR) superfamily that modulate neuronal excitability and development, synaptic plasticity and neurotransmitter release underlying optimal cognitive function [8]. Group 1 mGluRs are predominantly expressed in the postsynaptic somatodendritic regions, especially in brain areas highly responsive to psychostimulants including Nucleus accumbens (NAc), whereas Groups II and III mGluRs are mainly localized presynaptically on axons and axonal terminals [13], [14]
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