PKMζ is necessary for long‐term depression and long‐term potentiation in the medial prefrontal cortex

PKMζ is an atypical, constitutively active protein kinase found exclusively in the nervous system. PKMζ is an AMPA receptor (AMPAR) trafficking protein that is involved in the insertion of GluA2-containing AMPARs in the synapse. As the trafficking of GluA2-containing AMPARs is central to both long-term depression (LTD) and long-term potentiation (LTP), PKMζ should play a critical role in both forms of plasticity. However, the exact role for PKMζ depends on brain region and sex. In the hippocampus of male mice, PKMζ knockout mice exhibit normal LTP due to compensatory mechanisms. However, altering PKMζ in wild-type mice with PKMζ-antisense or allosteric inhibitors results in deficits in late-LTP in the region. In contrast, LTD in the nucleus accumbens following PKMζ knockout is disrupted in male but not female mice. This suggests that the mechanisms driving plasticity may be regionally distinct and influenced by sex. The current study aimed to examine the role of PKMζ in both LTP and LTD in a third brain region to determine if the effects of PKMζ are region-specific or if the role of PKMζ differs based on form of plasticity. Using a constitutive PKMζ knockout model, we recorded LTD and LTP from the medial prefrontal cortex (mPFC) of male and female mice. We found that find both male and female PKMζ knockout mice exhibit blunted LTD and LTP indicating that PKMζ is necessary for both LTD and LTP in the mPFC. Together, this suggests that the role of PKMζ in plasticity is not uniform throughout the brain. KEY POINTS: Male and female PKMζ knockout mice have blunted LTD in the medial prefrontal cortex (mPFC). Male and female PKMζ knockout mice have blunted LTP in the mPFC. Male but not female PKMζ knockout mice have reduced glutamatergic transmission in the mPFC. PKMζ is necessary for mPFC synaptic plasticity in the mPFC in both male and female mice.