Cocaine Exposure Modulates Perineuronal Nets and Synaptic Excitability of Fast-Spiking Interneurons in the Medial Prefrontal Cortex

ABSTRACTPerineuronal nets (PNNs) surrounding fast-spiking, parvalbumin (PV) inhibitory interneurons are vital for providing excitatory:inhibitory balance within cortical circuits, and this balance is impaired in disorders such as schizophrenia, autism spectrum disorder, and substance use disorders. These disorders are also associated with altered diurnal rhythms, yet few studies have examined the diurnal rhythms of PNNs or PV cells. We measured the intensity and number of PV cells and PNNs labeled with Wisteria floribunda agglutinin (WFA) in the rat prelimbic medial prefrontal cortex (mPFC) at Zeitgeber times (ZT) ZT0, 6, 12, and 18. We also measured the oxidative stress marker 8-oxo-deoxyguanosine (8-oxo-dG). Relative to ZT0, the intensities of PNN and PV staining were increased in the dark (active) phase compared with the light (inactive) phase. The intensity of 8-oxo-dG was decreased from ZT0 at all time points (ZT6,12,18), in both PV cells and non-PV cells. To examine corresponding changes in inhibitory and excitatory inputs, we measured GAD 65/67 and vGlut1 puncta apposed to PV cells with and without PNNs. Relative to ZT6, there were more excitatory puncta on PV cells surrounded by PNNs at ZT18, but no changes in PV cells devoid of PNNs. No changes in inhibitory puncta were observed. Whole-cell slice recordings in fast-spiking (PV) cells with PNNs showed an increased ratio of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor:N-methyl-D-aspartate receptor (AMPA:NMDA) at ZT18 vs. ZT6. The number of PV cells and co-labeled PV/PNN cells containing the transcription factor orthodenticle homeobox 2 (OTX2), which maintains PNNs, showed a strong trend toward an increase from ZT6 to ZT18. These diurnal fluctuations in PNNs and PV cells are expected to alter cortical excitatory:inhibitory balance and provide new insights into treatment approaches for diseases impacted by imbalances in sleep and circadian rhythms.

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014 Diurnal changes in perineuronal nets and parvalbumin neurons in the rat medial prefrontal cortex

SLEEP ◽

10.1093/sleep/zsab072.013 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A7-A8

Author(s):

Barbara Sorg ◽

John Harkness ◽

Angela Gonzalez ◽

Priyanka Bushana ◽

Emily Jorgensen ◽

...

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Diurnal Rhythms ◽

Oxidative Stress Marker ◽

Perineuronal Nets ◽

Diurnal Changes ◽

Strong Trend ◽

Fast Spiking ◽

Diurnal Fluctuations ◽

Alcohol And Drug Abuse

Abstract Introduction Perineuronal nets (PNNs) surrounding fast-spiking, parvalbumin (PV) interneurons provide excitatory:inhibitory balance within cortical circuits. This balance is impaired in several disorders that are also associated with altered diurnal rhythms, yet few studies examined diurnal rhythms of PNNs or PV cells. Methods We measured the intensity and number of PV cells and PNNs labeled with Wisteria floribunda agglutinin (WFA) and also the oxidative stress marker 8-oxo-deoxyguanosine (8-oxo-dG) in rat prelimbic medial prefrontal cortex (mPFC) at Zeitgeber times (ZT) ZT0, 6, 12, and 18. To examine changes in inhibitory and excitatory inputs to PV cells, we measured GAD 65/67 and vGLUT1 puncta apposed to PV cells with and without PNNs. Whole-cell slice recordings in fast-spiking (PV) cells with PNNs was conducted to determine the ratio of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor:N-methyl-D-aspartate receptor (AMPA:NMDA) at ZT18 vs. ZT6. Finally, the number of PV cells and PV/PNN cells containing orthodenticle homeobox 2 (OTX2), which maintains PNNs, was also assessed. Results Relative to ZT0, the intensities of PNN and PV labeling were increased in the dark compared with the light phase. The intensity of 8-oxo-dG was decreased from ZT0 at all times. There were more excitatory puncta on PV cells with PNNs at ZT18 vs. ZT6, but no changes in PV cells without PNNs and no changes in inhibitory puncta. There was an increased AMPA:NMDA ratio at ZT18 vs. ZT6. The number of PV cells and PV/PNN cells containing OTX2 showed a strong trend toward an increase from ZT6 to ZT18, with no differences in non-PV-containing cells. Conclusion Diurnal fluctuations in PNNs and PV cells alter cortical excitatory:inhibitory balance. Detailed understanding of how these fluctuations are regulated should provide new insights into treatments for diseases impacted by disturbances in sleep and circadian rhythms. Ongoing studies are examining diurnal fluctuations in downstream signaling after PNN removal. Support (if any) Washington State University Alcohol and Drug Abuse Research Program, NIH GM134789 (JHH); NIH DA033404 (BAS), DA040965 (BAS, TEB, SAA); NIH NS078498 (JPW); NIH P30 NS061800 (SAA); and Agence Nationale de la Recherche ANR-18-CE16-0013-01 (AP and AAD).

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Repeated cocaine exposure increases fast-spiking interneuron excitability in the rat medial prefrontal cortex

Journal of Neurophysiology ◽

10.1152/jn.00596.2012 ◽

2013 ◽

Vol 109 (11) ◽

pp. 2781-2792 ◽

Cited By ~ 9

Author(s):

Emilie Campanac ◽

Dax A. Hoffman

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Pyramidal Neurons ◽

Input Resistance ◽

Compensatory Mechanism ◽

Cocaine Exposure ◽

Membrane Excitability ◽

Chronic Cocaine ◽

Fast Spiking ◽

Circuit Output

The medial prefrontal cortex plays a key role in cocaine addiction. However, how chronic cocaine exposure affects cortical networks remains unclear. Most studies have focused on layer 5 pyramidal neurons (the circuit output), while the response of local GABAergic interneurons to cocaine remains poorly understood. Here, we recorded from fast-spiking interneurons (FS-IN) after repeated cocaine exposure and found altered membrane excitability. After cocaine withdrawal, FS-IN showed an increase in the number of spikes evoked by positive current injection, increased input resistance, and decreased hyperpolarization-activated current. We also observed a reduction in miniature excitatory postsynaptic currents, whereas miniature inhibitory postsynaptic current activity was unaffected. We show that, in animals with cocaine history, dopamine receptor D2 activation is less effective in increasing FS-IN intrinsic excitability. Interestingly, these alterations are only observed 1 wk or more after the last cocaine exposure. This suggests that the dampening of D2-receptor-mediated response may be a compensatory mechanism to rein down the excitability of FS-IN.

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