# D1/D5 receptor activation promotes long‐term potentiation and synaptic tagging/capture in hippocampal area CA2

## TL;DR

This study shows that activating dopamine D1/D5 receptors in the hippocampus's CA2 area enhances synaptic plasticity and could explain social memory issues in neuropsychiatric diseases.

## Contribution

The paper reveals a novel role of D1/D5 receptor activation in overcoming plasticity resistance in CA2 synapses.

## Key findings

- D1/D5 receptor activation primes CA2 synapses in an NMDAR- and protein synthesis-dependent manner.
- SKF-38393 relieves plasticity resistance in SC-CA2 synapses at 50 μm concentration.
- D1R activation promotes synaptic plasticity via PKA signaling in CA2.

## Abstract

Hippocampal area CA2 plays an important role in social memory formation. However, CA2 is characterised by plasticity‐resistant Schaffer Collateral‐CA2 (SC‐CA2) synapses and highly plastic entorhinal cortex‐CA2 (EC‐CA2) synapses. Despite abundant dopaminergic input, the relationship between dopamine signalling and area CA2 synaptic plasticity remains unexplored. Here, we show that SKF‐38393‐mediated dopamine D1‐like receptor (dopamine D1 and D5 receptors (D1R and D5R)) activation differentially primes CA2 inputs in an N‐methyl‐D‐aspartate receptor (NMDAR)‐ and protein synthesis‐dependent manner. We defined an inverted U‐shape relationship between SKF‐38393 concentration and EC‐CA2 potentiation. Additionally, we observed a priming effect on SC‐CA2 plasticity with 50 μm SKF‐38393, relieving plasticity resistance. We also demonstrated that this effect follows canonical protein kinase A (PKA) signalling. Collectively, our results show that D1R activation primes the CA2 for synaptic plasticity. Thus, we propose a link between neuropsychiatric diseases related to impaired dopamine transmission and deficits in hippocampus‐dependent social memory.

Activation of dopamine receptor D1 (D1R) stimulates PKA and ERK pathways via dissociation of stimulatory and olfactory G protein alpha subunits (Gαs/olf). PKA relieves striatal‐enriched protein tyrosine phosphatase (STEP) inhibition of ERK, promoting cyclic adenosine monophosphate response element‐binding protein (CREB)‐driven transcription of plasticity‐related proteins (PRPs). PKA also enhances calcium ion (Ca2+) influx at α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPAR) and N‐methyl‐D‐aspartate receptors (NMDAR), lowering long‐term potentiation (LTP) thresholds and inducing synaptic plasticity.