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• W1520271859 abstract "•Maternal deprivation (MD) did not affect AMPAR-mediated synaptic transmission in VTA DA neurons•MD induced both pre- and postsynaptic GABAergic LTD•MD induced GABAergic metaplasticity through disruption of AKAP150 signaling•GABAergic synaptic and AKAP signaling deficits were rescued by HDAC inhibition Adverse early-life experiences such as child neglect and abuse increase the risk of developing addiction and stress-related disorders through alterations in motivational systems including the mesolimbic dopamine (DA) pathway. Here we investigated whether a severe early-life stress (i.e., maternal deprivation, MD) promotes DA dysregulation through an epigenetic impairment of synaptic plasticity within ventral tegmental area (VTA) DA neurons. Using a single 24-hr episode of MD and whole-cell patch clamp recording in rat midbrain slices, we show that MD selectively induces long-term depression (LTD) and shifts spike timing-dependent plasticity (STDP) toward LTD at GABAergic synapses onto VTA DA neurons through epigenetic modifications of postsynaptic scaffolding A-kinase anchoring protein 79/150 (AKAP79/150) signaling. Histone deacetylase (HDAC) inhibition rescues GABAergic metaplasticity and normalizes AKAP signaling in MD animals. MD-induced reversible HDAC-mediated GABAergic dysfunction within the VTA may be a mechanistic link for increased propensity to mental health disorders following MD. Adverse early-life experiences such as child neglect and abuse increase the risk of developing addiction and stress-related disorders through alterations in motivational systems including the mesolimbic dopamine (DA) pathway. Here we investigated whether a severe early-life stress (i.e., maternal deprivation, MD) promotes DA dysregulation through an epigenetic impairment of synaptic plasticity within ventral tegmental area (VTA) DA neurons. Using a single 24-hr episode of MD and whole-cell patch clamp recording in rat midbrain slices, we show that MD selectively induces long-term depression (LTD) and shifts spike timing-dependent plasticity (STDP) toward LTD at GABAergic synapses onto VTA DA neurons through epigenetic modifications of postsynaptic scaffolding A-kinase anchoring protein 79/150 (AKAP79/150) signaling. Histone deacetylase (HDAC) inhibition rescues GABAergic metaplasticity and normalizes AKAP signaling in MD animals. MD-induced reversible HDAC-mediated GABAergic dysfunction within the VTA may be a mechanistic link for increased propensity to mental health disorders following MD. Child neglect and abuse are pervasive and costly public health concerns with serious negative long-term effects on child health and development, including an increased risk of mental health disorders and substance abuse in later life (Rentesi et al., 2013Rentesi G. Antoniou K. Marselos M. Syrrou M. Papadopoulou-Daifoti Z. Konstandi M. Early maternal deprivation-induced modifications in the neurobiological, neurochemical and behavioral profile of adult rats.Behav. Brain Res. 2013; 244: 29-37Crossref PubMed Scopus (52) Google Scholar). Understanding the consequences of child abuse and neglect on neural processes that shape memories and guide behaviors is critical for developing psychological and pharmacological interventions to improve outcomes of these children. Synaptic plasticity (changes in synaptic strength) is an experience-dependent learning mechanism of the brain used to process and store information vital for survival. However, prolonged exposure to stress and addictive drugs dysregulates synaptic plasticity within mesocorticolimbic brain systems (i.e., the brain reward pathway), thereby shaping pathological learning of anxiety-, depressive-, and addictive-like behaviors (Sinha, 2008Sinha R. Chronic stress, drug use, and vulnerability to addiction.Ann. N Y Acad. Sci. 2008; 1141: 105-130Crossref PubMed Scopus (1118) Google Scholar). A single 24-hr episode of early maternal deprivation (MD) in rodents has been widely used to model severe early-life stress such as child abuse and neglect. This model was shown to promote behavioral impairments with disturbances in stress responsiveness that resemble anxiety-, depressive-, psychotic-, and addictive-like symptoms (Faturi et al., 2010Faturi C.B. Tiba P.A. Kawakami S.E. Catallani B. Kerstens M. Suchecki D. Disruptions of the mother-infant relationship and stress-related behaviours: altered corticosterone secretion does not explain everything.Neurosci. Biobehav. Rev. 2010; 34: 821-834Crossref PubMed Scopus (57) Google Scholar, Gruss et al., 2008Gruss M. Braun K. Frey J.U. Korz V. Maternal separation during a specific postnatal time window prevents reinforcement of hippocampal long-term potentiation in adolescent rats.Neuroscience. 2008; 152: 1-7Crossref PubMed Scopus (49) Google Scholar, Kember et al., 2012Kember R.L. Dempster E.L. Lee T.H. Schalkwyk L.C. Mill J. Fernandes C. Maternal separation is associated with strain-specific responses to stress and epigenetic alterations to Nr3c1, Avp, and Nr4a1 in mouse.Brain Behav. 2012; 2: 455-467Crossref PubMed Scopus (106) Google Scholar, Marco et al., 2009Marco E.M. Adriani W. Llorente R. Laviola G. Viveros M.P. Detrimental psychophysiological effects of early maternal deprivation in adolescent and adult rodents: altered responses to cannabinoid exposure.Neurosci. Biobehav. Rev. 2009; 33: 498-507Crossref PubMed Scopus (72) Google Scholar, Nishi et al., 2014Nishi M. Horii-Hayashi N. Sasagawa T. Effects of early life adverse experiences on the brain: implications from maternal separation models in rodents.Front Neurosci. 2014; 8: 166Crossref PubMed Scopus (148) Google Scholar, Roceri et al., 2002Roceri M. Hendriks W. Racagni G. Ellenbroek B.A. Riva M.A. Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus.Mol. Psychiatry. 2002; 7: 609-616Crossref PubMed Scopus (384) Google Scholar). During MD, the hypothalamic-pituitary-adrenal stress response is persistently upregulated and the ability of MD animals to cope with stressful situations is significantly diminished, with symptoms evident from adolescence and into adulthood (Marco et al., 2009Marco E.M. Adriani W. Llorente R. Laviola G. Viveros M.P. Detrimental psychophysiological effects of early maternal deprivation in adolescent and adult rodents: altered responses to cannabinoid exposure.Neurosci. Biobehav. Rev. 2009; 33: 498-507Crossref PubMed Scopus (72) Google Scholar). Moreover, MD rodents and adolescent human subjects reporting low parental care show heightened impulsivity and exhibit anxiety-like behaviors associated with increased levels of monoamine neurotransmitters including DA in the mesocorticolimbic dopaminergic pathway (Ellenbroek et al., 2005Ellenbroek B.A. Derks N. Park H.J. Early maternal deprivation retards neurodevelopment in Wistar rats.Stress. 2005; 8: 247-257Crossref PubMed Scopus (79) Google Scholar, Hall et al., 1999Hall F.S. Wilkinson L.S. Humby T. Robbins T.W. Maternal deprivation of neonatal rats produces enduring changes in dopamine function.Synapse. 1999; 32: 37-43Crossref PubMed Scopus (179) Google Scholar, Llorente et al., 2010Llorente R. O’Shea E. Gutierrez-Lopez M.D. Llorente-Berzal A. Colado M.I. Viveros M.P. Sex-dependent maternal deprivation effects on brain monoamine content in adolescent rats.Neurosci. Lett. 2010; 479: 112-117Crossref PubMed Scopus (36) Google Scholar, Pruessner et al., 2004Pruessner J.C. Champagne F. Meaney M.J. Dagher A. Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: a positron emission tomography study using [11C]raclopride.J. Neurosci. 2004; 24: 2825-2831Crossref PubMed Scopus (575) Google Scholar, Rentesi et al., 2013Rentesi G. Antoniou K. Marselos M. Syrrou M. Papadopoulou-Daifoti Z. Konstandi M. Early maternal deprivation-induced modifications in the neurobiological, neurochemical and behavioral profile of adult rats.Behav. Brain Res. 2013; 244: 29-37Crossref PubMed Scopus (52) Google Scholar). The mesocorticolimbic dopaminergic pathway originating from the ventral tegmental area (VTA) controls mood and motivation. DA release from the VTA is a key detector of reward response and is involved in reward-related learning. Dysregulation of DA signaling from the VTA has been linked to neuropsychiatric disorders. However, whether early MD affects the reward learning processes and synaptic function in the VTA is unknown. Strengthening (long-term potentiation, LTP) and weakening (long-term depression, LTD) of excitatory and inhibitory synapses onto VTA DA neurons critically influences DA cell firing and release (Dacher and Nugent, 2011bDacher M. Nugent F.S. Opiates and plasticity.Neuropharmacology. 2011; 61: 1088-1096Crossref PubMed Scopus (49) Google Scholar). Investigations are currently aiming to identify patterns of learning-related DA neuronal activity and signaling mechanisms that drive activity-dependent plasticity of VTA DA neurons. Such knowledge will lead to a better understanding of the function DA neurons serve in reward-related behaviors and how the brain reward circuitry is remodeled by stress and addictive drugs. There is an increasing interest in the functional roles of synaptic plasticity at inhibitory GABAergic synapses in brain circuits, particularly the brain reward pathway, where GABAergic dysfunction significantly contributes to the pathophysiology of depression, addiction, anxiety, and schizophrenia (Dacher and Nugent, 2011bDacher M. Nugent F.S. Opiates and plasticity.Neuropharmacology. 2011; 61: 1088-1096Crossref PubMed Scopus (49) Google Scholar, Gao and Bao, 2011Gao S.F. Bao A.M. Corticotropin-releasing hormone, glutamate, and γ-aminobutyric acid in depression.Neuroscientist. 2011; 17: 124-144Crossref PubMed Scopus (57) Google Scholar). Epigenetic mechanisms regulate gene expression without altering the DNA sequence. Many of these are activated by early environmental experiences and shape neuronal plasticity, and hence behavior. Epigenetic modifications in the VTA such as DNA methylation are critical for the formation of reward learning (Day et al., 2013Day J.J. Childs D. Guzman-Karlsson M.C. Kibe M. Moulden J. Song E. Tahir A. Sweatt J.D. DNA methylation regulates associative reward learning.Nat. Neurosci. 2013; 16: 1445-1452Crossref PubMed Scopus (167) Google Scholar). Chromatin modifications by enzymes such as histone deacetylases (HDACs) also alter gene expression in neurons and neuroplasticity underlying memory formation (Abel and Zukin, 2008Abel T. Zukin R.S. Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders.Curr. Opin. Pharmacol. 2008; 8: 57-64Crossref PubMed Scopus (416) Google Scholar, Haggarty and Tsai, 2011Haggarty S.J. Tsai L.H. Probing the role of HDACs and mechanisms of chromatin-mediated neuroplasticity.Neurobiol. Learn. Mem. 2011; 96: 41-52Crossref PubMed Scopus (78) Google Scholar). GABAA receptors (GABAAR) are epigenetically regulated in response to early-life stress and addictive drugs (Arora et al., 2013Arora D.S. Nimitvilai S. Teppen T.L. McElvain M.A. Sakharkar A.J. You C. Pandey S.C. Brodie M.S. Hyposensitivity to gamma-aminobutyric acid in the ventral tegmental area during alcohol withdrawal: reversal by histone deacetylase inhibitors.Neuropsychopharmacology. 2013; 38: 1674-1684Crossref PubMed Scopus (43) Google Scholar, Kennedy et al., 2013Kennedy P.J. Feng J. Robison A.J. Maze I. Badimon A. Mouzon E. Chaudhury D. Damez-Werno D.M. Haggarty S.J. Han M.H. et al.Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation.Nat. Neurosci. 2013; 16: 434-440Crossref PubMed Scopus (129) Google Scholar). GABAAR signaling in DA neurons plays a key role in reward-motivated learning (Laviolette and van der Kooy, 2001Laviolette S.R. van der Kooy D. GABA(A) receptors in the ventral tegmental area control bidirectional reward signalling between dopaminergic and non-dopaminergic neural motivational systems.Eur. J. Neurosci. 2001; 13: 1009-1015Crossref PubMed Scopus (119) Google Scholar, Parker et al., 2011Parker J.G. Wanat M.J. Soden M.E. Ahmad K. Zweifel L.S. Bamford N.S. Palmiter R.D. Attenuating GABA(A) receptor signaling in dopamine neurons selectively enhances reward learning and alters risk preference in mice.J. Neurosci. 2011; 31: 17103-17112Crossref PubMed Scopus (40) Google Scholar). However, it is unknown which epigenetic mechanisms influence GABAergic plasticity and mediate maladaptive forms of such plasticity in the VTA. Because of the importance of GABAAR signaling in reward learning and the critical implications of epigenetic regulation of memory, stress-related disorders, schizophrenia, and addiction (Abel and Zukin, 2008Abel T. Zukin R.S. Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders.Curr. Opin. Pharmacol. 2008; 8: 57-64Crossref PubMed Scopus (416) Google Scholar, Costa et al., 2003Costa E. Grayson D.R. Guidotti A. Epigenetic downregulation of GABAergic function in schizophrenia: potential for pharmacological intervention?.Mol. Interv. 2003; 3: 220-229Crossref PubMed Scopus (52) Google Scholar, Rudenko and Tsai, 2014Rudenko A. Tsai L.H. Epigenetic regulation in memory and cognitive disorders.Neuroscience. 2014; 264: 51-63Crossref PubMed Scopus (43) Google Scholar), we hypothesized that MD would trigger HDAC-mediated epigenetic changes in the gene encoding the scaffold protein AKAP150 (human 79/rodent 150, also referred to as AKAP5) in the VTA. AKAP150 is an important integrator of signaling molecules to glutamatergic and GABAergic synapses that control the synaptic trafficking underlying synaptic plasticity (Dacher et al., 2013Dacher M. Gouty S. Dash S. Cox B.M. Nugent F.S. A-kinase anchoring protein-calcineurin signaling in long-term depression of GABAergic synapses.J. Neurosci. 2013; 33: 2650-2660Crossref PubMed Scopus (30) Google Scholar, Jurado et al., 2010Jurado S. Biou V. Malenka R.C. A calcineurin/AKAP complex is required for NMDA receptor-dependent long-term depression.Nat. Neurosci. 2010; 13: 1053-1055Crossref PubMed Scopus (89) Google Scholar, Lu et al., 2007Lu Y. Allen M. Halt A.R. Weisenhaus M. Dallapiazza R.F. Hall D.D. Usachev Y.M. McKnight G.S. Hell J.W. Age-dependent requirement of AKAP150-anchored PKA and GluR2-lacking AMPA receptors in LTP.EMBO J. 2007; 26: 4879-4890Crossref PubMed Scopus (142) Google Scholar, Lu et al., 2008Lu Y. Zhang M. Lim I.A. Hall D.D. Allen M. Medvedeva Y. McKnight G.S. Usachev Y.M. Hell J.W. AKAP150-anchored PKA activity is important for LTD during its induction phase.J. Physiol. 2008; 586: 4155-4164Crossref PubMed Scopus (58) Google Scholar, Sanderson et al., 2012Sanderson J.L. Gorski J.A. Gibson E.S. Lam P. Freund R.K. Chick W.S. Dell’Acqua M.L. AKAP150-anchored calcineurin regulates synaptic plasticity by limiting synaptic incorporation of Ca2+-permeable AMPA receptors.J. Neurosci. 2012; 32: 15036-15052Crossref PubMed Scopus (98) Google Scholar). Epigenetic changes leading to altered AKAP signaling would in turn selectively reduce GABAergic inhibition in the VTA and thus contribute to the development of later psychopathology following MD. Indeed, AKAP proteins are epigenetically regulated (Choi et al., 2004Choi M.C. Jong H.S. Kim T.Y. Song S.H. Lee D.S. Lee J.W. Kim T.Y. Kim N.K. Bang Y.J. AKAP12/Gravin is inactivated by epigenetic mechanism in human gastric carcinoma and shows growth suppressor activity.Oncogene. 2004; 23: 7095-7103Crossref PubMed Scopus (84) Google Scholar, Reissner et al., 2011Reissner K.J. Uys J.D. Schwacke J.H. Comte-Walters S. Rutherford-Bethard J.L. Dunn T.E. Blumer J.B. Schey K.L. Kalivas P.W. AKAP signaling in reinstated cocaine seeking revealed by iTRAQ proteomic analysis.J. Neurosci. 2011; 31: 5648-5658Crossref PubMed Scopus (36) Google Scholar), and global knockout of AKAP150 is associated with synaptic and behavioral abnormalities (Tunquist et al., 2008Tunquist B.J. Hoshi N. Guire E.S. Zhang F. Mullendorff K. Langeberg L.K. Raber J. Scott J.D. Loss of AKAP150 perturbs distinct neuronal processes in mice.Proc. Natl. Acad. Sci. USA. 2008; 105: 12557-12562Crossref PubMed Scopus (130) Google Scholar). Therefore, we tested whether a single 24-hr episode of MD, on postnatal day 9 (P9), would affect synaptic function and plasticity of VTA DA neurons through reversible epigenetic modifications of genes involved in AKAP signaling and learning mechanisms in the VTA. Our results suggest that MD induces an aberrant GABAergic metaplasticity through reversible epigenetic mechanisms that alter the AKAP signaling associated with memory formation in the VTA. Repeated or prolonged exposure to stress increases DA levels in projection areas of the VTA, leading to heightened impulsivity and anxiety-like behaviors from adolescence to adulthood (Meaney et al., 2002Meaney M.J. Brake W. Gratton A. Environmental regulation of the development of mesolimbic dopamine systems: a neurobiological mechanism for vulnerability to drug abuse?.Psychoneuroendocrinology. 2002; 27: 127-138Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar). MD-induced changes in synaptic transmission onto VTA DA neurons are likely to occur but have yet to be described. Stress effectively modulates synaptic plasticity at both glutamatergic and GABAergic synapses onto DA neurons (Niehaus et al., 2010Niehaus J.L. Murali M. Kauer J.A. Drugs of abuse and stress impair LTP at inhibitory synapses in the ventral tegmental area.Eur. J. Neurosci. 2010; 32: 108-117Crossref PubMed Scopus (101) Google Scholar, Saal et al., 2003Saal D. Dong Y. Bonci A. Malenka R.C. Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons.Neuron. 2003; 37: 577-582Abstract Full Text Full Text PDF PubMed Scopus (879) Google Scholar); thus, we first tested whether MD induces an excitatory LTP in VTA DA neurons. Although acute stress potentiates glutamatergic synapses onto VTA DA neurons (Saal et al., 2003Saal D. Dong Y. Bonci A. Malenka R.C. Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons.Neuron. 2003; 37: 577-582Abstract Full Text Full Text PDF PubMed Scopus (879) Google Scholar), we found that α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor (AMPAR)/N-methyl-D-aspartate receptor(NMDAR) ratios (AMPAR/NMDAR ratios) (commonly used as a reliable measurement for glutamatergic plasticity) measured in VTA DA neurons from 14- to 21-day-old non-MD and MD rats showed no significant difference (Figures 1A–1C, non-MD, n = 8: 0.86 ± 0.23; MD, n = 9: 0.81 ± 0.20; unpaired Student’s t test: p = 0.87501). To further test whether MD induced changes in the function and/or surface expression of AMPARs (postsynaptic plasticity) or glutamate release from glutamatergic terminals (presynaptic plasticity) onto VTA DA neurons, we recorded AMPAR-mediated miniature EPSCs (mEPSCs) in the presence of the sodium channel blocker tetrodotoxin (TTX, 1 μM) in slices prepared from non-MD and MD rat pups. We found that the average and cumulative probability of AMPAR-mediated mEPSC amplitudes and frequencies did not differ between MD and non-MD rats, suggesting that MD did not change AMPAR function in VTA DA neurons (Figures 1F–1K, non-MD, n = 8: 13.47 ± 0.7 pA, 3.848 ± 0.36 Hz; MD, n = 9: 12.75 ± 0.59 pA, 3.249 ± 0.36 Hz; unpaired Student’s t tests: p = 0.19573 for amplitude, p = 0.12262 for frequency; Kolmogorov-Smirnov [KS] tests for cumulative distribution curves: p = 0.927 for amplitude, p = 0.989 for frequency). MD alters AMPAR and NMDAR subunit composition in the hippocampus (Pickering et al., 2006Pickering C. Gustafsson L. Cebere A. Nylander I. Liljequist S. Repeated maternal separation of male Wistar rats alters glutamate receptor expression in the hippocampus but not the prefrontal cortex.Brain Res. 2006; 1099: 101-108Crossref PubMed Scopus (89) Google Scholar, Roceri et al., 2002Roceri M. Hendriks W. Racagni G. Ellenbroek B.A. Riva M.A. Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus.Mol. Psychiatry. 2002; 7: 609-616Crossref PubMed Scopus (384) Google Scholar, Rodenas-Ruano et al., 2012Rodenas-Ruano A. Chávez A.E. Cossio M.J. Castillo P.E. Zukin R.S. REST-dependent epigenetic remodeling promotes the developmental switch in synaptic NMDA receptors.Nat. Neurosci. 2012; 15: 1382-1390Crossref PubMed Scopus (151) Google Scholar), and given that such changes in AMPAR subunit composition could occur without alteration in overall synaptic strength measured by mEPSC amplitude or AMPAR/NMDAR ratios, we recorded evoked AMPAR-mediated EPSCs at different holding potentials while intracellularly applying spermine. This allowed us to detect the relative contribution of inwardly rectifying Ca2+-permeable/GluA2-lacking AMPARs to synaptic transmission. AMPAR rectification was unaltered after MD, and EPSC IV plots were linear in both groups. This is consistent with the presence of GluA2 in most synaptic AMPARs in MD rats, similar to non-MD rats (Figures 1D and 1E, AMPAR rectification indices: non-MD, n = 5: 1.444 ± 0.23; MD, n = 5: 1.4677 ± 0.33; unpaired Student’s t test: p = 0.9548; two-way ANOVA for IV curves, F(1,5) = 0.01102, p = 0.92047). Acute stress was previously shown to block a presynaptic form of LTP at GABAergic synapses onto VTA DA neurons (Niehaus et al., 2010Niehaus J.L. Murali M. Kauer J.A. Drugs of abuse and stress impair LTP at inhibitory synapses in the ventral tegmental area.Eur. J. Neurosci. 2010; 32: 108-117Crossref PubMed Scopus (101) Google Scholar, Nugent et al., 2007Nugent F.S. Penick E.C. Kauer J.A. Opioids block long-term potentiation of inhibitory synapses.Nature. 2007; 446: 1086-1090Crossref PubMed Scopus (252) Google Scholar). We tested the effects of MD on GABAAR-mediated miniature IPSCs (mIPSCs) to identify whether MD per se induced any form of GABAergic plasticity. We found that the frequency and amplitude of mIPSCs were significantly reduced in MD compared to non-MD rats. (Figures 2A and 2B , non-MD, n = 6: 30.25 ± 0.2.44 pA, 4.92 ± 0.38 Hz; MD, n = 8: 22.33 ± 1.06 pA, 3.42 ± 0.45 Hz; unpaired Student’s t tests: p = 0.0067 for amplitude, p = 0.0316 for frequency; KS tests for cumulative distribution curves: p < 0.0001 for amplitude, p = 0.036 for frequency). These findings suggest that MD suppressed both pre- and postsynaptic function of GABAergic synapses onto VTA DA neurons. Previous experiences such as in vivo exposure to addictive drugs, stress, and sensory or visual deprivation can change the ability of synapses to undergo subsequent plasticity in response to LTP and LTD induction protocols. This phenomenon is referred as metaplasticity (Abraham and Bear, 1996Abraham W.C. Bear M.F. Metaplasticity: the plasticity of synaptic plasticity.Trends Neurosci. 1996; 19: 126-130Abstract Full Text PDF PubMed Scopus (1224) Google Scholar). Although traditional induction protocols of LTP and LTD have been successfully used to induce synaptic plasticity, near-coincidental pre- and postsynaptic firing can also trigger a form of plasticity where the precise timing and patterns of spikes are critical (i.e., spike timing-dependent plasticity, STDP). This is an attractive induction protocol since it mimics naturally occurring neuronal activity required for plasticity (Caporale and Dan, 2008Caporale N. Dan Y. Spike timing-dependent plasticity: a Hebbian learning rule.Annu. Rev. Neurosci. 2008; 31: 25-46Crossref PubMed Scopus (1088) Google Scholar). Recently, we showed that GABAergic synapses onto VTA DA neurons were capable of exhibiting a bidirectional postsynaptic Hebbian STDP (i.e., STD-LTPGABA and STD-LTDGABA in response to repeated pre-post spike pairings at positive interval of +15 ms and post-pre spike pairings at negative interval of −5 ms, respectively). Interestingly, this STDP was triggered by correlated activities of the presynaptic glutamatergic input and postsynaptic DA cells where NMDARs served as coincident detectors for this heterosynaptic plasticity (Kodangattil et al., 2013Kodangattil J.N. Dacher M. Authement M.E. Nugent F.S. Spike timing-dependent plasticity at GABAergic synapses in the ventral tegmental area.J. Physiol. 2013; 591: 4699-4710Crossref PubMed Scopus (18) Google Scholar). Given that early MD is a potent stressor, we hypothesized that MD induces metaplastic changes in GABAergic synapses that subsequently alter the response of DA neurons to STDP protocols. Therefore, we used STDP protocols to induce GABAergic STDP in midbrain slices prepared from non-MD and MD rats. To define the temporal window for STDP induction, we tested three additional STDP protocols with different time intervals (−15 ms, +5 ms, and +25 ms). Data for time courses of STDP at these three additional intervals are shown in Figure S1, and the averaged magnitudes of synaptic change for all STDP experiments with a given Δt are depicted in Figure 3E. Pairings at a negative interval of −15 ms and a positive interval of +25 ms did not induce any form of plasticity in slices from non-MD or MD rats, demonstrating a short temporal window for GABAergic STDP in the VTA. Interestingly, a robust STD-LTDGABA was induced in response to pre-post positive pairing at +5 ms intervals in slices from MD rats while non-MD rats did not exhibit STDP at this time interval. Moreover, slices prepared from MD animals did not exhibit STD-LTPGABA at +15 ms (in fact, the polarity of STDP in response to pre-post pairings at this interval shifted toward LTD), whereas non-MD rats showed robust STD-LTPGABA. STD-LTDGABA (induced in response to negative pairings at −5 ms) was also absent in slices from MD rats, whereas plasticity was intact in slices from non-MD rats. Altogether these data suggest that MD-induced metaplastic changes impaired the ability of GABAergic synapses to exhibit normal bidirectional STDP, narrowed the STDP window, and shifted STDP toward LTD. In Figure 3, the time courses of STDP are only shown at the negative timing of −5 ms and positive timing of +15 ms. In the remainder of the paper, only these two intervals are used for STDP induction and are designated as “pre-post” for positive timing of +15 ms and “post-pre” for negative timing of −5 ms (Figures 3A and 3D, for STD-LTDGABA, non-MD, n = 6: 64% ± 2.4% of pre-STDP values, F11.53,57.67 = 11.09, p < 0.0001, MD, n = 7: 96% ± 2.7% of pre-STDP values, F9.43, 37.73 = 0.478, p = 0.886, unpaired Student’s t test for STD-LTDGABA between MD and non-MD rats, p < 0.001; Figures 3B and 3C for STD-LTPGABA: non-MD, n = 8: 151% ± 8.4% of pre-STDP values, F5.26,36.87 = 3.369, p = 0.012, MD, n = 8: 85% ± 21% of pre-STDP values, F3.32,23.26 = 3.368, p = 0.032, unpaired Student’s t test for STD-LTPGABA between MD and non-MD rats, p < 0.001; Figure 3E shows the temporal windows of STDP in non-MD and MD rats). Although we identified a shift in GABAergic STDP toward LTD following MD, the cellular and molecular mechanisms underlying this metaplasticity remained unknown. To identify potential mechanisms of metaplasticity, we first characterized STDP. Previously we discovered that the AKAP150 complex selectively controlled GABAAR trafficking-mediated GABAergic plasticity in the VTA. Postsynaptic disruption of Protein Kinase A (PKA)-AKAP association or PKA inhibition induced a calcineurin (CaN)-dependent, long-lasting reduction in synaptic GABAA responses that mimicked LTDGABA (induced in response to a traditional LTD pairing protocol) without affecting AMPAR-mediated glutamatergic transmission in VTA DA neurons (Dacher et al., 2013Dacher M. Gouty S. Dash S. Cox B.M. Nugent F.S. A-kinase anchoring protein-calcineurin signaling in long-term depression of GABAergic synapses.J. Neurosci. 2013; 33: 2650-2660Crossref PubMed Scopus (30) Google Scholar, Dacher and Nugent, 2011aDacher M. Nugent F.S. Morphine-induced modulation of LTD at GABAergic synapses in the ventral tegmental area.Neuropharmacology. 2011; 61: 1166-1171Crossref PubMed Scopus (34) Google Scholar). Here, we determined whether the PKA-AKAP-CaN complex also underlies GABAergic STDP. Consistent with our previous results, intra-pipette AKAP inhibitor Ht31 (1 μM) resulted in a remarkably rapid rundown of synaptic transmission, whereas control peptide Ht31p (1 μM) did not (Figure 4A, Ht31p cells, n = 19: 93% ± 4% of the first 5-min baseline values, F10.387, 46.161 = 1.035, p = 0.44; Ht31 cells, n = 14: 58% ± 1% of the first 5-min baseline values, F15.902, 47.707 = 6.614, p < 0.00001). Once Ht31-induced depression plateaued, STDP protocols were used to trigger STD-LTPGABA or STD-LTDGABA. Intra-pipette Ht31 prevented the induction of STD-LTPGABA, while Ht31p-filled cells expressed STD-LTPGABA (Figures 4B and 4C, Ht31p cells, n = 7: 140% ± 2% of pre-STDP values, F10.127,9.922 = 6.124, p < 0.0001; Ht31 cells, n = 7: 99.3% ± 2.8% of pre-STDP values, F11.78,47.151 = 0.93, p = 0.453). Moreover, intra-pipette Ht31-induced rundown occluded STD-LTDGABA, whereas Ht31p did not affect the plasticity (Figure 5A, Ht31p cells, n = 12: 71% ± 2% of pre-STDP values, F9.192, 45.962 = 6.316, p < 0.0001; Ht31 cells, n = 7: 105% ± 3% of pre-STDP values, F14.945, 59.779 = 0.878, p = 0.591), suggesting that the disruption of association between PKA and AKAP is sufficient to induce STD-LTDGABA. Consistent with our previous results, postsynaptic inhibition of PKA by intracellular inclusion of PKI(6-22) (10 μM), a membrane-impermeant PKA inhibitor, significantly reduced IPSC amplitude (Figures 4D and 4E; PKI cells, n = 6: 63% ± 2% of the first 5-min baseline values, F11.37,45.48 = 21.145, p < 0.0001). PKI(6-22)-induced depression of IPSCs not only inhibited STD-LTPGABA but also shifted the polarity of plasticity toward LTD (Figures 4E and 4F; control STD-LTP for PKI(6-22), n = 7: 121% ± 1.4% of pre-STDP values, F8.58,34.34 = 3.356, p = 0.005; PKI(6-22) cells, n = 6: 76.6% ± 1.1% of pre-STDP values, F16.95,50.86 = 3.14" @default.
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