fm1-43 and 2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline

Degeneration of dopamine (DA) neurons in Parkinson's disease (PD) causes hypokinesia, but DA replacement therapy can elicit exaggerated voluntary and involuntary behaviors that have been attributed to enhanced DA receptor sensitivity in striatal projection neurons. Here we reveal that in hemiparkinsonian mice, striatal D1 receptor-expressing medium spiny neurons (MSNs) directly projecting to the substantia nigra reticulata (SNr) lose tonic presynaptic inhibition by GABAB receptors. The absence of presynaptic GABAB response potentiates evoked GABA release from MSN efferents to the SNr and drives motor sensitization. This alternative mechanism of sensitization suggests a synaptic target for PD pharmacotherapy.

Topics: Adrenergic Agents; Animals; Bacterial Proteins; Channelrhodopsins; Corpus Striatum; Disease Models, Animal; Dopamine; Excitatory Amino Acid Antagonists; GABA Agents; GABAergic Neurons; gamma-Aminobutyric Acid; Humans; Inhibitory Postsynaptic Potentials; Luminescent Proteins; Medial Forebrain Bundle; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Oxidopamine; Parkinsonian Disorders; Presynaptic Terminals; Pyridinium Compounds; Quaternary Ammonium Compounds; Quinoxalines; Substantia Nigra

Neurons engage compensatory, homeostatic synaptic changes to maintain their overall firing rate. We examined the induction and expression of a persistent presynaptic adaptation. We explored the effect of mild extracellular potassium elevation to increase hippocampal pyramidal neuron spiking over a physiological range. With several days of mild depolarization, glutamate release adapted, as revealed by an increased mismatch between the number of active, FM1-43-positive, glutamatergic synapses and the total number of synapses defined by vesicular glutamate transporter-1 antibody staining. Surprisingly, the adaptation of glutamate terminals was all-or-none; recycling vesicle pool size at remaining active synapses was not significantly altered by the adaptation. Tetrodotoxin (TTX), but not postsynaptic receptor blockade, reversed depolarization-induced adaptation, and TTX added to normal incubation medium increased the number of active synapses, suggesting that normal spiking activity sustains a steady-state percentage of inactive terminals. Chronic mild depolarization depressed EPSCs and decreased the size of the readily releasable pool of vesicles (RRP). Several hours of 10 Hz electrical stimulation also depressed the RRP size, confirming that spiking alone induces adaptation and that strong stimulation induces more rapid presynaptic adaptation. Despite the importance of RRP alteration to the adaptation, ultrastructural experiments revealed no changes in docked or total synaptic vesicle numbers. Furthermore, alpha-latrotoxin induced vesicle release at adapted synapses, consistent with the idea that adaptation resulted from changes in vesicle priming. These results show that glutamatergic neurotransmission persistently adapts to changes in electrical activity over a wide physiological range.

Topics: 2-Amino-5-phosphonovalerate; Action Potentials; Animals; Animals, Newborn; Dose-Response Relationship, Drug; Electric Stimulation; Excitatory Amino Acid Antagonists; Hippocampus; Immunohistochemistry; Microscopy, Electron, Transmission; Neural Inhibition; Neurons; Organ Culture Techniques; Patch-Clamp Techniques; Potassium Chloride; Pyridinium Compounds; Quaternary Ammonium Compounds; Quinoxalines; Rats; Synapses; Synaptic Transmission; Synaptic Vesicles; Vesicular Glutamate Transport Protein 1