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.
Key points• GABAergic synapses onto ventral tegmental area (VTA) dopamine neurons express a bidirectional spike timing-dependent plasticity (STDP; both long-term potentiation and long-term depression).• GABAergic synapses in the VTA obey the classical Hebbian learning rules of STDP.• GABAergic STDP in VTA dopamine neurons is expressed postsynaptically.• GABAergic STDP is heterosynaptic and NMDA receptor dependent.• Pairing of pre-and postsynaptic spiking is necessary for induction of GABAergic STDP.Abstract Persistent changes in excitatory and inhibitory synaptic strengths to the ventral tegmental area (VTA) dopamine (DA) neurons in response to addictive drugs may underlie the transition from casual to compulsive drug use. While an enormous amount of work has been done in the area of glutamatergic plasticity of the VTA, little is known regarding the learning rules governing GABAergic plasticity in the VTA. Spike timing-dependent plasticity, STDP, has attracted considerable attention primarily due to its potential roles in processing and storage of information in the brain and there is emerging evidence for the existence of STDP at inhibitory synapses. We therefore used whole-cell recordings in rat midbrain slices to investigate whether near-coincident pre-and postsynaptic firing induces a lasting change in synaptic efficacy of VTA GABAergic synapses. We found that a Hebbian form of STDP including long-term potentiation (LTP) and long-term depression (LTD) can be induced at GABAergic synapses onto VTA DA neurons and relies on the precise temporal order of pre-and postsynaptic spiking. Importantly, GABAergic STDP is heterosynaptic (NMDA receptor dependent): triggered by correlated activities of the presynaptic glutamatergic input and postsynaptic DA cells. GABAergic STDP is postsynaptic and has an associative component since pre-or postsynaptic spiking per se did not induce STDP. STDP of GABAergic synapses in the VTA provides physiologically relevant forms of inhibitory plasticity that may underlie natural reinforcement of reward-related behaviours. Moreover, this form of inhibitory plasticity may mediate some of the reinforcing, aversive and addictive properties of drugs of abuse.
Chemokines, a family member of cytokines, have been shown to playa major role in central nervous system inflammation. Among other chemokines, CXCR3 and its ligand CXCLIO are involved in the pathophysiology of several neuroinflammatory conditions. Most of these conditions are also associated with an increased incidence of seizure or epilepsy. Using age-matched wild-type (WT), as well as CXCR3-receptor-deficient (CXCR3-KO) mice, the present study aimed to investigate the effect of the chemokine CXCLIO and its receptor CXCR3 on synaptic plasticity as well as neuronal activities in hippocampal brain slices. Using field potential and intracellular recordings, the effect of exogenous CXCLIO on tetanus-induced long-term potentiation (LTP) as well as the neuronal spike activity was evaluated in hippocampal CAl area. Exogenous application of CXCLIO enhanced LTP in WT mice, whereas it exerted no significant effect on CXCR3-KO mice. During intracellular recordings of spontaneous spike activity, exogenous application of CXCLIO significantly enhanced the amplitude, duration, and after-hyperpolarization of action potentials in slices obtained from WT mice compared to CXCR3-KO mice. In addition, CXCR3-KO mice exhibited a lower GABAA-mediated excitation in hippocampal CAl neurons compared to WT mice. These data show that the inflammatory chemokine CXCLIO, probably via its receptor CXCR3, modulates neuronal activity and synaptic plasticity in the hippocampus. CXCLIO may be involved in seizures observed during neuroinflammatory diseases such as meningitis and encephalitis.Multiple clinical observations and experimental studies suggest that inflammatory processes in the central nervous system may play a role in the pathogenesis of epileptic seizures, status epilepticus and chronic epilepsy. Inflammatory diseases of the brain, such as viral encephalitis and bacterial meningoencephalitis, are often associated with epileptic seizures or status epilepticus during the acute phase or recurrent epileptic seizures as a persisting sequalae. The underlying epileptogenic mechanisms are a matter of ongoing research. There are numerous studies investigating the role of certain components such as cytokines of the complex inflammatory response (1,2). Among all cytokines, those which are
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