Differential involvement of Ca2+/calmodulin-dependent protein kinases and mitogen-activated protein kinases in the dopamine D1/D5 receptor-mediated potentiation in hippocampal CA1 pyramidal neurons

•D1/D5 receptor-dependent LTP (DA-LTP) in CA1 region is MEK/MAPK pathway dependent.•Here we studied the differential role of CaMKs and MEKs during DA-LTP.•With weak dopaminergic activation, both CaMKII and MEKs were necessary for DA-LTP.•During stronger dopaminergic activation, the role of CaMKII becomes dispensable.•MEK/MAPK activation is crucial both during weaker and stronger activation of DA-LTP.

Dopaminergic neurotransmission modulates and influences hippocampal CA1 synaptic plasticity, learning and long-term memory mechanisms. Investigating the mechanisms involved in the slow-onset potentiation induced by the dopamine D1/D5 receptor agonists in hippocampal CA1 region, we have reported recently that it could play a role in regulating synaptic cooperation and competition. We have also shown that a sustained activation of MEK/MAP kinase pathway was involved in the maintenance of this long-lasting potentiation (Shivarama Shetty, Gopinadhan, & Sajikumar, 2016). However, the molecular aspects of the induction of dopaminergic slow-onset potentiation are not known. Here, we investigated the involvement of MEK/MAPK pathway and Ca2+-calmodulin-dependent protein kinases (CaMKII and CaMKIV) in the induction and maintenance phases of the D1/D5 receptor-mediated slow-onset potentiation. We report differential involvement of these kinases in a dose-dependent manner wherein at weaker levels of dopaminergic activation, both CaMKII and MEK1/2 activation is necessary for the establishment of potentiation and with sufficiently stronger dopaminergic activation, the role of CaMKII becomes dispensable whereas MEK activation remains crucial for the long-lasting potentiation. The results are interesting in view of the involvement of the hippocampal dopaminergic system in a variety of cognitive abilities including memory formation and also in neurological diseases such as Alzheimer's disease and Parkinson's disease.