PKN1 promotes synapse maturation by inhibiting mGluR-dependent silencing through neuronal glutamate transporter activation

Abstract

Abnormal metabotropic glutamate receptor (mGluR) activity could cause brain disorders; however, its regulation has not yet been fully understood. Here, we report that protein kinase N1 (PKN1), a protein kinase expressed predominantly in neurons in the brain, normalizes group 1 mGluR function by upregulating a neuronal glutamate transporter, excitatory amino acid transporter 3 (EAAT3), and supports silent synapse activation. Knocking out PKN1a, the dominant PKN1 subtype in the brain, unmasked abnormal input-nonspecific mGluR-dependent long-term depression (mGluR-LTD) and AMPA receptor (AMPAR) silencing in the developing hippocampus. mGluR-LTD was mimicked by inhibiting glutamate transporters in wild-type mice. Knocking out PKN1a decreased hippocampal EAAT3 expression and PKN1 inhibition reduced glutamate uptake through EAAT3. Also, synaptic transmission was immature; there were more silent synapses and fewer spines with shorter postsynaptic densities in PKN1a knockout mice than in wild-type mice. Thus, PKN1 plays a critical role in regulation of synaptic maturation by upregulating EAAT3 expression.

Developmental pyrethroid exposure disrupts molecular pathways for MAP kinase and circadian rhythms in mouse brain

“…Protein kinase C (PKC) has a long-established role in long-term potentiation and NMDA regulation(56–58). Protein kinase N, a member of the PKC superfamily, directly interacts with AKT (the central node of our multi-omics network) and may have a specific role in synapse maturation(59, 60). The ERK/MAP kinase cascade regulates transcriptional events related to synaptic plasticity(61); and in addition to being a high-confidence differentially active kinase, ERK substrates were enriched among genes of interest, and ERK was the second most central node in our multi-omics network.…”

“…Protein kinase C (PKC) has a long-established role in longterm potentiation and NMDA regulation [51][52][53] . Protein kinase N, a member of the PKC superfamily, directly interacts with AKT (the primary hub of our multi-omics network) and may have a specific role in synapse maturation 54,55 . The ERK/MAP kinase cascade regulates transcriptional events related to synaptic plasticity 56 .…”

PKN1 Is a Novel Regulator of Hippocampal GluA1 Levels

“…Recently it was shown that PKN1 promotes synapse maturation by inhibiting type I metabotropic glutamate receptor-dependent long term depression through regulation of excitatory amino acid transporter 3 (EAAT3) in area CA1 (Yasuda et al, 2020). Knockdown of PKN1 to 1/10th of WT levels results in immature synaptic transmission, more silent synapses and fewer spines with shorter postsynaptic densities in juvenile CA1 neurons.…”

Neural mechanism underlies CYLD modulation of morphology and synaptic function of medium spiny neurons in dorsolateral striatum

“…Dendrite arborization and spine density were quantified by an independent investigator. Dendritic spines were classified based on the spine length and spine head width, as follows: mushroom (with spine head, head width/length ratio > 0.5); thin (with spine head, length > 1.2 μm, head width/length ratio < 0.5); stubby (length < 1.2 μm, with spine head, head width/length ratio < 0.5; without head, not applicable); filopodia (without spine head, length > 1.2 μm) ( Llano et al, 2015 ; Yasuda et al, 2020 ). In addition to the four classical spine subtypes, we define varicosity as dendritic segments displaying varicose swellings (dendritic diameter > 2 μm) with spine loss ( Westrum et al, 1964 ; Isokawa, 1997 ; Swann et al, 2000 ; Maiti et al, 2015 ).…”