Up and Down Regulation of Synaptic Strength at Hippocampal to Prefrontal Cortex Synapses

Abstract

Specific patterns of stimulation applied in the ventral hippocampus produce long-term potentiation (LTP) or long-term depression of stimulated synapses in the prefrontal cortex (PFC, or prelimbic area) in vivo, and these different forms of plasticity are reversible. LTP induction is dependent on NMDA receptors and the activation of the cAMP-dependent kinase, PKA. The mesocortical dopamine input is an important determinant in synaptic plasticity at the hippocampal to PFC synapses. An increase in prefrontal dopamine as well as a local stimulation of D1 receptors is able to induce a long-lasting enhancement of hippocampal-prefrontal LTP, whereas a significant cortical dopamine depletion or a specific blockade of D1, but not D2, receptors results in a dramatic impairment of cortical LTP. Together, these data demonstrate that DA and D1 receptors are necessary for the expression of synaptic plasticity in PFC. In addition, the stimulation paradigm used to induce this NMDA-dependent LTP causes an increase in dopamine release in PFC, suggesting a direct role of dopamine in the induction mechanisms. We propose a cooperative action of D1 and NMDA receptors in the induction mechanisms of prefrontal LTP involving mostly PKA-dependent mechanisms. These results are significant for current understanding of prefrontal memory mechanisms and their abnormalities in schizophrenia. In recent studies, we have shown that LTP at hippocampal to PFC synapses is dramatically impaired by stress, suggesting a role of this limbic/cortical circuit in depression.KeywordsLong-term potentiationlong-term depressionprelimbic areadopamine D 1 dopamine D 2 PKAworking memorystress