Research within the Laboratory for Integrative Neuroscience, Section on Synaptic Pharmacology, continues to focus on mechanisms underlying neuromodulation and plasticity and the effects of alcohol and other drugs of abuse on these neuronal functions. Our main interest is the function of the dorsal striatum (DS), a brain region involved in action control and selection, as well as action learning. Presynaptic Calcium and Striatal Synaptic Function. One of our main research foci is on presynaptic modulation and plasticity at synapses in the dorsal striatum. We are interested in these mechanisms not only because they are involved in control of brain circuitry important for action production, but also because presynaptic mechanisms are implicated in diseases caused by striatal dysfunction. One of the major neurological problems stemming from altered synaptic transmission is Parkinsons Disease (PD). In PD midbrain neurons that innervate dorsal striatum are lost, and this leads to bradykinesia, akinesia, cognitive impairments, and eventually is lethal. Recent studies using rodent PD models indicate that impaired release of the neurotransmitter dopamine (DA) precedes overt death of dopaminergic neurons. Indeed, using mice genetically-engineered to express the human alpha-synuclein gene carrying a PD-causing mutation show impaired DA release as early as 1 month of age, coinciding with the onset of movement problems in these animals. We wish to determine what mechanisms underlie this impairment of release. Depolarization-induced influx of calcium is a necessary step in excitation-secretion coupling that produces the bulk of neurotransmitter release at presynaptic axon terminals in neurons. Thus, we want to determine if altered presynaptic calcium influx/handling is associated with the decreased DA release we have observed in the mutant alpha-synuclein-expressing mice. To this end, Dr. Huaibin Cai at NIA generated mice in which the calcium-sensing protein GCaMP3 is expressed in dopaminergic neurons, but not in striatal neurons or in other neurons that supply afferent input to striatum. In brain slices from these mice we are using photometric techniques to measure calcium transients produced by activation of dopaminergic afferents to dorsal striatum. In mice that do no not express the mutant alpha-synuclein, these presynaptic calcium transients require activation of the same types of voltage-gated calcium channels implicated in dopamine release. The transients are also sensitive to modulation by presynaptic receptors known to affect release of this neurotransmitter. Thus, we are confident that this technique provides information about calcium entry and handling in the presynaptic elements of dopaminergic neurons in striatum. Using this technique in mice expressing the human alpha-synuclein mutant protein we find deficiencies in calcium handling within the presynaptic elements, especially when axons are activated with bursts of stimulation. Current work is aimed at determining if altered calcium handling contributes to the malfunction and eventual death of these terminals. We can also use GCaMP sensor proteins to examine calcium transients in other types of presynaptic inputs to striatum, and this will allow us to determine the role of presynaptic calcium changes in modulation and long-lasting synaptic plasticity at striatal synapses. To this end, we have expressed GCaMP5 and 6 in cortical neurons that innervate dorsal striatum. Using the photometric approach in brain slices we have observed that presynaptic calcium transients in these corticostriatal inputs can be modulated by a variety of G-protein-coupled receptors that are known to alter neurotransmitter release. We are currently attempting to determine if sustained suppression of presynaptic calcium transients underlies long-term synaptic depression (LTD) at these corticostriatal synapses. Ethanol actions at striatal GABAergic synapses We are also continuing our studies of ethanol (EtOH) effects on GABAergic synaptic transmission in dorsolateral (DLS) and dorsomedial striatum (DMS) using brain slice electrophysiological recording. Our observation that EtOH inhibits GABAergic synaptic transmission in DLS medium spiny neurons (MSNs) via a presynaptic mechanism, while potentiating transmission in DMS MSNs, suggests differential mechanisms of EtOH action in the two striatal subregions. In these experiments we have measured spontaneously-occurring miniature inhibitory postsynaptic currents (mIPSCs). The effects of EtOH reverse rapidly when the drug is washed from the brain slice, at least at low-moderate EtOH concentrations. The opposing effects in DLS and DMS are surprising, and may indicate that EtOH suppresses the output of the DMS that is important for goal-directed actions, while enhancing the output of DLS which is involved in habit formation. We are continuing this line of investigation using optogenetic techniques to determine if these differential EtOH effects occur at different afferent inputs to MSNs. The two predominant GABAergic inputs to striatal MSNs come from axon collaterals of other MSNs that synapse mainly on the MSN dendrites, and from the fast-spiking interneurons that synapse mainly near the MSN soma. We can activate the two GABAergic inputs independently by expressing channel rhodopsin 2 selectively in the two neuronal subtypes and activating this channel with light. This produces optically-evoked IPSCs (oIPSCs) recorded from MSNs. Using this approach, we find that EtOH inhibits oIPSCs from both neuronal subtypes in the DLS. Interestingly, the effects of EtOH are not reversible upon washing out the drug at any concentration. This finding suggests that EtOH may itself produce LTD at GABAergic synapses. Experiments are currently underway to determine if neurotransmitters other than GABA are involved in this synaptic depression. Similar experiments are also ongoing in the DMS. Ultimately, we are interested in determining how these changes in GABAergic transmission contribute to intoxication, and habitual alcohol seeking.

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National Institute on Alcohol Abuse and Alcoholism
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Wilcox, Mark V; Cuzon Carlson, Verginia C; Sherazee, Nyssa et al. (2014) Repeated binge-like ethanol drinking alters ethanol drinking patterns and depresses striatal GABAergic transmission. Neuropsychopharmacology 39:579-94
Crowley, Nicole A; Cody, Patrick A; Davis, Margaret I et al. (2014) Chronic methylphenidate exposure during adolescence reduces striatal synaptic responses to ethanol. Eur J Neurosci 39:548-56
Sgobio, Carmelo; Kupferschmidt, David A; Cui, Guohong et al. (2014) Optogenetic measurement of presynaptic calcium transients using conditional genetically encoded calcium indicator expression in dopaminergic neurons. PLoS One 9:e111749
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Parisiadou, Loukia; Yu, Jia; Sgobio, Carmelo et al. (2014) LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity. Nat Neurosci 17:367-76
Mathur, Brian N; Tanahira, Chiyoko; Tamamaki, Nobuaki et al. (2013) Voltage drives diverse endocannabinoid signals to mediate striatal microcircuit-specific plasticity. Nat Neurosci 16:1275-83
Lovinger, David M; Roberto, Marisa (2013) Synaptic effects induced by alcohol. Curr Top Behav Neurosci 13:31-86
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Cuzon Carlson, Verginia C; Mathur, Brian N; Davis, Margaret I et al. (2011) Subsets of Spiny Striosomal Striatal Neurons Revealed in the Gad1-GFP BAC Transgenic Mouse. Basal Ganglia 1:201-211
Godlewski, Grzegorz; Offertaler, Laszlo; Osei-Hyiaman, Douglas et al. (2009) The endogenous brain constituent N-arachidonoyl L-serine is an activator of large conductance Ca2+-activated K+ channels. J Pharmacol Exp Ther 328:351-61

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