The conserved MAP3K12/Dual Leucine Zipper Kinase (DLK) plays versatile roles in neuronal development, axon injury and stress responses, and neurodegeneration, depending on cell-type and cellular contexts. Emerging evidence implicates abnormal DLK signaling in several neurodegenerative diseases. However, our understanding of the DLK-dependent gene network in the central nervous system remains limited. Here, we investigated the roles of DLK in hippocampal glutamatergic neurons using conditional knockout and induced overexpression mice. We found that dorsal CA1 and dentate gyrus neurons are vulnerable to elevated expression of DLK, while CA3 neurons appear less vulnerable. We identified the DLK-dependent translatome that includes conserved molecular signatures and displays cell-type specificity. Increasing DLK signaling is associated with disruptions to microtubules, potentially involving STMN4. Additionally, primary cultured hippocampal neurons expressing different levels of DLK show altered neurite outgrowth, axon specification, and synapse formation. The identification of translational targets of DLK in hippocampal glutamatergic neurons has relevance to our understanding of selective neuron vulnerability under stress and pathological conditions.

The reward and novelty-related neuromodulator dopamine plays an important role in hippocampal long-term memory, which is thought to involve protein-synthesis-dependent synaptic plasticity. However, the direct effects of dopamine on protein synthesis, and the functional implications of newly synthesised proteins for synaptic plasticity, have not yet been investigated. We have previously reported that timing-dependent synaptic depression (t-LTD) can be converted into potentiation by dopamine application during synaptic stimulation (Brzosko et al., 2015) or postsynaptic burst activation (Fuchsberger et al., 2022). Here, we show that dopamine increases protein synthesis in mouse hippocampal CA1 neurons, enabling dopamine-dependent long-term potentiation (DA-LTP), which is mediated via the Ca²⁺-sensitive adenylate cyclase (AC) subtypes 1/8, cAMP, and cAMP-dependent protein kinase (PKA). We found that neuronal activity is required for the dopamine-induced increase in protein synthesis. Furthermore, dopamine induced a protein-synthesis-dependent increase in the AMPA receptor subunit GluA1, but not GluA2. We found that DA-LTP is absent in GluA1 knock-out mice and that it requires calcium-permeable AMPA receptors. Taken together, our results suggest that dopamine together with neuronal activity controls synthesis of plasticity-related proteins, including GluA1, which enable DA-LTP via a signalling pathway distinct from that of conventional LTP.