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Published in final edited form as: J Physiol. 2025 Oct 18;604(3):1272–1281. doi: 10.1113/JP289373

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

Alyssa R Kniffin 1, Erin A English 1, Lisa A Briand 1
PMCID: PMC12965130  NIHMSID: NIHMS2135052  PMID: 41109691

Abstract

PKMζ is an atypical, constitutively active protein kinase found exclusively in the brain. PKMζ is an AMPA receptor trafficking protein that is involved in the insertion of GluA2-containing AMPRAs in the synapse. As the trafficking of GluA2-containing 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 wildtype mice with PKMζ-antisense or allosteric inhibitors result 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 in PKMζ knockout mice indicating that PKMζ is necessary for both LTD and LTP in the mPFC. Together, this suggests that the role of PKMζ in plasticity are not uniform across brain region or form of plasticity.

Graphical Abstract

graphic file with name nihms-2135052-f0004.jpg

Genetic deletion of PKMζ dampens both long-term depression (LTD) and long-term potentiation (LTP) in the medial prefrontal cortex in both male and female mice. LTD was induced using low frequency stimulation (LFS) and LTP was induced using theta burst stimulation (TBS). Here we represent this effect of genetic knockout on LTD and LTP and provide location of field recording in the medial prefrontal cortex though stimulation of layer II/III and recording from layer V.

1. Introduction

Post-synaptic AMPARs mediate nearly all fast excitatory neurotransmission and are composed of four types of subunits (GluA1-GluA4), which combine to form tetramers (Hollmann & Heinemann, 1994; Sobolevsky et al., 2009; Henley et al., 2011; Henley & Wilkinson, 2013; Gan et al., 2015; Morise et al., 2019). The dynamic alteration of both the composition and amount of AMPAR at the synapse determines the state of potentiation at the synapse (Malinow, 2003; Bissen et al., 2019; de León-López et al., 2025). The atypical protein kinase C (PKC), PKMζ, is poised to play a unique role in this trafficking due to its ability to remain constitutively active (Hernandez et al., 2003). This is due to the elimination of the autoinhibitory pseudosubstrate of the (PKCζ regulatory domain (Hernandez et al., 2003). PKMζ maintains GluA2-containing AMPARs at the synaptic membrane by preventing AMPAR endocytosis and lateral diffusion (Yao et al., 2008; Yu et al., 2017; Patel & Zamani, 2021).

At the synapse, AMPAR number and composition are dependent on the rate of endocytosis and exocytosis (Turrigiano, 2000; Barry & Ziff, 2002; Bredt & Nicoll, 2003; Anggono & Huganir, 2012). More specifically, GluA2-containing AMPARs have been shown to be the most associated with these changes. GluA2-containing AMPARs are typically calcium impermeable (CI-AMPARs) ion channels that make up the majority of AMPARs in mature neurons (Greger et al., 2003; Man, 2011). Generally, during long term depression (LTD), there is enhanced AMPAR endocytosis while during long term potentiation (LTP), more AMPARs are inserted or maintained at the synapse (Carroll et al., 1999; Beattie et al., 2000; Makino & Malinow, 2009; Chater & Goda, 2014; Sumi & Harada, 2020). The synthesis of synaptic plasticity related proteins is involved in the maintenance of both LTD and LTP, separating early phase plasticity from late phase (Costa-Mattioli et al., 2009). The bidirectional changes in receptor density during LTD and LTP implies that the relative activity of PKMζ should impact both forms of plasticity.

PKMζ knockout modulates synaptic plasticity in the nucleus accumbens (Knouse et al., 2023). Male mice genetically lacking PKMζ exhibited blunted LTD in response to low frequency stimulation in the accumbens, an effect not seen in female mice. Similarly, altering GluA2 trafficking via glutamate receptor-interacting protein (GRIP) abolishes LTD in the nucleus accumbens (Briand et al., 2014). As opposed to the clear role for GluA2 trafficking and PKMζ in the accumbens, there are different roles observed in the hippocampus. A PKMζ knockout study in the hippocampus indicated that these genetic knockouts exhibit normal LTP (Volk et al., 2013). However, others have shown that genetic knockouts have compensatory PKC isoforms that are upregulated, occluding the role of PKMζ in LTP in the hippocampus (Wang et al., 2016; Sheng et al., 2017) . Further, under wildtype conditions PKMζ may be more critical for late-phase LTP while the PKC i/y isoforms mediate early LTP (Li et al., 2017; Tsokas et al., 2024). While the role of PKMζ in the hippocampus has been studied extensively, these studies excluded female mice. In combination with studies in the nucleus accumbens, it is possible that either PKMζ has different roles in LTD or LTP depending on brain region, or that female mice may utilize PKMζ differently than males.

The current paper aims to examine both forms of plasticity in the same brain region in both sexes to determine if the effects of PKMζ are region- or sex-specific and or if the role of PKMζ differs based on form of plasticity. The medial prefrontal cortex (mPFC) is a region that displays both LTD and LTP and receives input from both the nucleus accumbens and hippocampus, making it an interesting target for investigation. Using a constitutive PKMζ knockout model, we recorded LTD and LTP from the mPFC of wildtype and PKMζ knockout male and female mice.

2. Methods

2.1. Ethical approval

All procedures were approved by the Temple University Animal Care and Use Committee (OLAW assurance #D16–00359(A3594–01) Expiration: 06/30/2028).

2.2. Subjects

The current study used wildtype male and female mice and constitutive PKMζ knockout mice as previously described (Volk et al., 2013). Heterozygous PKMζ KO mice on a C57BL/6J background were mated resulting in mutant and wildtype littermates. Animals were group housed throughout the experiments with food and water available ad libitum. All animals were housed in a temperature and humidity-controlled animal care facility.

2.3. Slice preparation

Mice were decapitated following cervical dislocation. The brain was removed and coronal slices (350 μm) containing the prefrontal cortex were cut with a Vibratome (VT10000S, Leica Microsystems) in an ice-cold artificial cerebrospinal fluid solution (ACSF), in which NaCl was replaced by an equimolar concentration of sucrose. ACSF consisted of (in mM): 128.2 NaCl, 2.9 KCl, 1.2 MgSO47H2O, 1.25 NaH2PO4, 28.8 NaHCO3, 2 CaCl2, 10 glucose (pH 7.2–7.4 when saturated with 95% O2/5% CO2). Slices were incubated in ACSF at 32–34 °C for 25 min and kept at 22–25 °C thereafter, until transferred to the recording chamber. The osmolarity of all solutions was 300–310 mOsm. Sliced were viewed using an infrared differential interference contrast optics under an upright microscope (Slice Scope Pro, Scientifica) with a 10x objective.

2.4. Electrophysiology

The submerged recording chamber was continuously perfused (2μl/ml) with oxygenated ACSF. Picrotoxin (100μM) was added to all solutions to block the GABAA receptor-mediated currents. Recording pipettes were pulled from borosilicate glass capillaries (World Precision Instruments) to a resistance of 1–2 MΩ when filled with extracellular solution. All recordings were conducted with MultiClamp700B amplifier (Molecular Devices). Field recordings. A glass capillary electrode filled with ACSF was placed within 100–300 μm from the recording electrode used to stimulate excitatory afferents in layer 2/3 and recorded from layer 5 of the mPFC in the prelimbic area. Long-term potentiation. The amplitude of current pulses was set at the intensity to evoke a 50% maximal response. After 10 minutes of stable responding, LTP was induced using a theta burst induction protocol (5 trains of 4 pulses with an inter-pulse interval of 10 seconds). Both field EPSP (fEPSP) slope (calculated over 1 ms after peak) and fEPSP amplitude were measured (graphs depict slope) from fEPSPs recorded at 0.05 Hz for 60 min following the theta burst protocol. Long-term depression. The amplitude of current pulses was set at the intensity to evoke a 50% maximal response. After 10 minutes of stable responding, LTD was induced using a low frequency stimulation (LFS), paired-pulse protocol (50 ms inter-pulse interval) consisting of a 1-Hz train of paired stimuli for 10 min. Both field EPSP (fEPSP) slope (calculated over 1 ms after peak) and fEPSP amplitude were measured (graphs depict slope) from fEPSPs recorded at 0.05 Hz for 60 min following the pairing protocol. Input-output curves. An input-output (I/O) curve was constructed by increasing the stimulation magnitude until a maximal fEPSP was obtained.

2.5. Data analysis

All analyses were performed using GraphPad Prism 9.0 software (GraphPad Software). Data were analyzed using two-tailed Student’s t-test or two-way ANOVA with Sidak’s post hoc tests as appropriate. Statistical significance for all tests was set at α = 0.05.

3. Results

3.1. PKMζ knockout alters LTD in female and male mice in the mPFC

We examined LTP in layer V pyramidal neurons in slice preparations from mouse mPFC. These neurons receive glutamatergic inputs and give rise to major cortical and subcortical projections many regions in the brain. We utilized a paired pulse LFS protocol that produced consistent, long-lasting reduction in signal in female (n=10) and male (n=7) wildtype mice [females: t(9)=4.945, p=0.0008; males t(6)=4.816, p=0.003, Fig 1A-B]. There were no significant differences between female and male wildtype mice [effect of sex: F(1,15)=1.201, p=0.29]. We found that neither female (n=10) nor male (n=11) PKMζ knockout mice exhibited a reduction in fEPSP slope following the LFS protocol [females: effect of genotype: F(1,17)=8.97, p=0.008, Fig 1A-B; males; effect of genotype: F(1,16)=4.91, p=0.042; Fig 1D-E]. Representative traces are shown in Fig 1C and 1F.

Figure 1. Medial prefrontal cortex LTD recordings in wildtype and PKMζ knockout by sex.

Figure 1.

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LTD induction by LFS (1 Hz train of paired stimuli for 10 minutes) is blunted in female (A) and male (D) PKMζ knockout animals compared to wildtype controls (female WT: n=10 slices/5 animals; female PKMζ KO: n=10 slices/4 mice; male WT: n=7 slices/4 mice; male PKMζ KO: n=11 slices/6 mice). Change in fEPSP slope over 1-hour post-LFS represented as % change from baseline shows LFS facilitates LTD in wildtypes and does not in PKMζ knockouts (B,E; mean ± SD). Representative pre- and post-LFS traces (C, F). *p<.05, **p<.01 effect of genotype.

3.2. PKMζ knockout alters LTP in female and male mice in the mPFC

In a separate cohort of mice, using the same slice preparation as used for LTD, we used a theta burst stimulation (TBS) protocol found to consistently produce a robust, long-lasting potentiation of fEPSPs in female (n=8) and male (n=13) wildtype mice [females: t(9)=2.686, p=0.25; males: t(12)=7.662, p= 0.0001]. As with LTD, female and male wildtype mice did not significantly differ in level of potentiation after TBS [effect of sex: F(1,21)=2.196, p=0.153]. To examine the role of PKMζ, we used slices from female (n=10) and male (n=8) constitutive PKMζ knockout mice. The magnitude of LTP was lower in both female and male PKMζ knockout mice, evidenced by a significantly reduced fEPSC slope compared to wildtype counterparts [females: effect of genotype: F(1,16)=7.91, p=0.013, Fig 2A-B; males: effect of genotype: F(1,19)=26.7, p=0.0001; Fig 2D-E]. Representative traces shown in Fig 2C and 2F.

Figure 2. Medial prefrontal cortex LTP recordings in wildtype and PKMζ knockouts by sex.

Figure 2.

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LTP induction by TBS (5 trains of 4 pulses with an inter-pulse interval of 10 seconds) is blunted in female (A) and male (D) PKMζ knockout animals compared to wildtype controls (female WT: n=10slices/5 mice; female PKMζ KO: n=8 slices/4 mice; male WT: n=13 slices/7 mice; male PKMζ KO: n=8 slices/4 animals). Change in fEPSP slope after 1-hour post-TBS is represented as % change from baseline and shows TBS facilitates LTP in wildtypes but not PKMζ knockouts (B,E; mean ± SD. Representative pre- and post-LFS traces (C, F). *p<.05, ***p<.0001 effect of genotype.

3.3. Male PKMζ knockout mice have reduced glutamatergic transmission

Using slices from the experiments above, we also examined excitability by taking input/output (I/O) curves by steadily increasing stimulation intensity once a stable field was found. No differences were found in I/O curve between female and male WT mice [effect of sex: F(1,29)=0.56, p=0.46]. However, a sex specific effect of PKMζ knockout was revealed. While no differences were found between wildtype and PKMζ knockout female mice [effect of genotype: t(14)=0.09, p=0.93, Fig 3A], male PKMζ knockout mice had significantly lower I/O curves compared to wildtype males [effect of genotype: F(1,18)=5.12, p=0.036, Fig 3B]. This indicates that male PKMζ knockout mice required a higher threshold for excitation.

Figure 3. Input/output curves plotted for PKMζ knockout compared to wildtype counterparts.

Figure 3.

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No differences in genotype were found in fEPSP slope in females (A; n=9–19 slices/group, mean ± SD). Male PKMζ knockout mice exhibited a reduced neuronal excitability compared to wildtype counterparts (B; n=8–12 slices/group, mean ± SD). *p<0.5.

4. Discussion

Glutamatergic pyramidal neurons in the mPFC are a key target for experience-dependent plasticity in response to both local and far-reaching input (DeFelipe & Fariñas, 1992; van Aerde & Feldmeyer, 2015). Our results demonstrate that PKMζ plays a critical role in synaptic plasticity in both males and females in the mPFC. Although PKMζ is critical for both LTP and LTD in the mPFC, this effect is not uniform amongst all brain regions and more work is needed to delineate the mechanism of action of PKMζ and whether it plays different roles in different regions (Volk et al., 2013; Knouse et al., 2023). PKMζ is thought to contribute to LTP via an increase in AMPAR anchoring and decrease in AMPAR endocytosis through PICK-1 and NSF- GluA2 interactions (Yao et al., 2008; Yu et al., 2017; Tsokas et al., 2024). These mechanisms would suggest that decreased PKMζ expression should result increased AMPAR endocytosis and thus, occlusion of LTD and a reduction in basal synaptic transmission. However, as we did not detect alterations in basal transmission, our results suggest that PKMζ may play a novel role in plasticity within the mPFC.

4.1. PKMζ is necessary for LTD in the mPFC

We find that mice genetically lacking PKMζ have significantly blunted LTD in the mPFC, regardless of biological sex. This experiment examines the role of PKMζ in LTD in the mPFC and points to a clear role in the trafficking of GluA2 AMPAR subunits in LFS-induced LTD. One other study has described AMPAR-mediated effects on LTD in the mPFC. Disrupting the interaction between the GluA2 AMPAR subunit and clathrin adaptor protein AP2, disrupts endocytosis mechanisms. This results in reduced ability for AMPAR endocytosis and effectively blocks LTD induction (Zhong et al., 2008). Our results further highlight the role of AMPAR trafficking in LTD in the mPFC, but may point to a different mechanism than expected.

LTD is a result of decrease synaptic strength, generally resulting from a reduction in AMPAR synaptic transmission at the post-synaptic membrane (O’Leary & Wyllie, 2008; Cao et al., 2023). AMPAR trafficking proteins are involved in the alteration of AMAPR composition or number at the synapse (Malinow & Malenka, 2002; Anggono & Huganir, 2012). Glutamate receptor interacting protein (GRIP) anchors GluA2 containing AMPAR at the synapses and works similarly to PKMζ. GRIP is necessary for LTD in the nucleus accumbens (Osten et al., 2000). Further, disrupting AMPAR trafficking by altering the function of protein interacting with C-kinase (PICK1) results in disrupted plasticity in the hippocampus (Terashima et al., 2008). PICK1 is involved in AMPAR internalization and is a key player in the recycling of AMPARs (Lu & Ziff, 2005; Hanley, 2008). Together, this shows the balance of AMPAR trafficking in and out of the synapse is critical in this form of plasticity. Our work builds on this body of literature indicating that PKMζ also play a critical role in LTD in the mPFC.

Our findings are distinct from previous studies examining the role of PKMζ in LTD in the nucleus accumbens (Knouse et al., 2023). There, the role of PKMζ in accumbal LTD is not uniform across biological sex. Male PKMζ knockout mice exhibit blunted accumbal LTD while female PKMζ knockout mice exhibited the opposite. However, both the effect of genotype and sex were abolished using a longer stimulation protocol, indicating PKMζ modulates the ability for synaptic connections to undergo LTD, as opposed to eliminating it altogether (Knouse et al., 2023). This effect might be specific to the nucleus accumbens as our results do not indicate a sex difference in the mPFC. Our study in combination with aforementioned study implies that PKMζ is not uniform across brain region. It has been shown that the level of PKMζ expression varies across brain region, which may be contributing differential roles in the nucleus accumbens vs mPFC.

4.2. PKMζ is necessary for LTP in the mPFC

Consistent with a general role for PKMζ in synaptic plasticity, we found that mice lacking PKMζ exhibit blunted LTP in the mPFC. As PKMζ is an AMPAR trafficking protein, this provides evidence that AMAPAR trafficking is a critical component of LTP in the mPFC. This result is in direct opposition to hippocampal recordings done with PKMζ knockout mice (Volk et al., 2013). Within the hippocampus, mice genetically lacking PKMζ exhibit normal synaptic transmission and LTP at the Schaffer collateral-CA1 synapses (Volk et al., 2013). In addition to conventional genetic knockout strategies, an inducible PKMζ knockdown model that results in approximately an 80% reduction in PKMζ in the dorsal hippocampus also reveals intact hippocampal LTP (Volk et al., 2013).

In combination with our results, this raises questions about region specific role for PKMζ in LTP. Synaptic transmission in the mPFC is extremely complex. The mPFC receives layer specific inputs from cortical and subcortical structures and is a central hub for information integration that is reliant on local circuits and long-range connections (Le Merre et al., 2021). Field recordings within the mPFC capture this non-specific summation of inputs, most likely in pyramidal neurons (Xu et al., 2019). The hippocampus functions as a closed circuit and has a less diverse set of functions (Naber et al., 2001). Plasticity within the hippocampus is incredibly robust and may be a much more redundant system. This would enable a wider range of stimulation protocols to elicit LTP (Carroll et al., 1999; Nicoll, 2017). This fundamental difference between the hippocampus and mPFC may underlie the differences in necessity of PKMζ driven LTP. However, it is likely that PKMζ is playing at least a supporting role in hippocampal synaptic plasticity. Inducing LTP in the hippocampus increases expression of PKMζ and is thought to maintain synaptic potentiation (Sacktor, 2008). Similarly, overexpression of PKMζ is sufficient to induce LTP (Schuette et al., 2016) and disruption of PKMζ function by altering PKMζ and anchoring protein KIBRA disrupts LTP (Tsokas et al., 2024). Therefore, the role of PKMζ in LTP in the mPFC and hippocampus may be different, or there may be more redundancy in the plasticity mechanism in the hippocampus that prevent PKMζ knockout from disrupting LTP.

4.3. Sex differences in the role of PKMζ

Sex specific role of PKMζ is complex and spans many areas of research. PKMζ plays a sex-specific role in visceral pain models. Global knockout of PKMζ reduces neuropathic pain in male rodents but has no effect on females (Nasir et al., 2016). Similarly, in a spatial memory task, male rats exhibit a positive correlation of synaptic PKMζ level with performance whereas stable levels of synaptic PKMζ were found in females (Sebastian et al., 2013). Various addiction studies have shown a sex-specific role for PKMζ in drug self-administration. Knocking out PKMζ in the nucleus accumbens produces an addictive phenotype in male mice but not females (McGrath et al., 2018). There is also evidence to suggest that PKMζ plays a sex-specific role in motivation for oxycodone (Knouse et al., 2024).

We found no differences in the role of PKMζ between male and female mice in LTD or LTP recordings in the mPFC. This indicates that regardless of the mechanisms that LTD and LTP, this response is disrupted when PKMζ is absent. These results are surprising due to the literature suggests PKMζ plays a more critical role in males in comparison to females. As mentioned above, PKMζ knockout blunts LTD in males but not females in the nucleus accumbens using a less intense stimulation protocol. Female PKMζ knockout mice expressed the opposite, a reduced thresholds for LTD compared to wildtypes (Knouse et al., 2023). Together, this shows that the role of PKMζ in synaptic plasticity is region-specific.

Our data on glutamatergic transmission may correlate with more profound role for PKMζ in male mice. We found that male PKMζ knockout mice had significantly reduced basal glutamatergic transmission compared to wildtypes as shown in the input output curve with no differences found in females. This result was interesting due to a lack of sex differences in LTD and LTP measures. It implies that PKMζ is a critical component of maintaining glutamatergic function in males but not females. A possibility is that females have additional systems in place that regulate AMPA receptor trafficking at basal levels of input such that PKMζ disruption does not alter glutamatergic transmission. Since most of the research and stimulation protocols were developed in male rodents, it is possible we are missing a critical mechanism that is exclusive to females that has not been captured.

5. Conclusion

LTD and LTP are both critical components in the brain’s ability to adapt to a changing environment (Bliss & Lomo, 1973; Lynch et al., 1977; Ito & Kano, 1982). Together, these mechanisms maintain glutamatergic homeostasis and sculpt neural circuits that allow for learning and memory (Bliss & Collingridge, 1993; Malenka & Bear, 2004; Citri & Malenka, 2008; Nabavi et al., 2014). While LTP is responsible for the strengthening of synaptic connections with repetitive input, LTD is essential for selectively weakening specific connections to allow others to persist (Hebb, 1949). Dysregulation in mPFC synaptic plasticity has been implicated in the pathophysiology of various illnesses and understanding the neurobiological underpinnings of these disorders may help aid the development of treatments (Kauer & Malenka, 2007; Kalivas, 2009; Volk et al., 2015). AMPAR trafficking is a critical component of many forms of synaptic plasticity (Malinow & Malenka, 2002; Kessels & Malinow, 2009). Here we show that AMPAR trafficking governed by PKMζ is not consistent across brain region in that it is necessary for LTD and LTP in the mPFC. Our work coincides with the modulatory role of PKMζ in the nucleus accumbens but opposes work in the hippocampus indicating PKMζ is not necessary for LTP. This lack of consistency poses an obstacle for the development of pharmacological treatments targeting PKMζ and/or AMPAR trafficking and highlights the necessity of using multiple brain regions in the study of synaptic plasticity.

Key Points.

  • Male and female PKMζ knockout mice have blunted LTD in the 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

Funding.

This work was supported by the National Institute on Drug Abuse (NIDA) Grant R01 DA047265 (L.A.B.), R01 DA049837 (L.A.B.), and T32 DA007237 (A.R.K).

Footnotes

6.

Additional Information

Ethics approval and consent to participate.

All procedures using experimental animals were approved by Temple’s Institutional Animal Care & Use Committee OLAW Assurance #D16–00359(A3594–01) Expiration: 06/30/2028.

Consent for publication.

All authors read and approved the final manuscript for publication.

Competing interests.

The authors declare no conflict of interest.

Availability of data and material.

The datasets used and/or analyzed during the current study are available on FigShare (Briand & Kniffin, 2025).

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets used and/or analyzed during the current study are available on FigShare (Briand & Kniffin, 2025).

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