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Addiction results from drug-elicited alterations of synaptic plasticity mechanisms in dopaminergic reward circuits. Impaired metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) and accumulation of synaptic Ca2+-permeable AMPA receptors (CP-AMPARs) following drug exposure have emerged as important mechanisms underlying drug craving and relapse. Here we show that repeated cocaine exposure in vivo causes transient but complete loss of mGluR1- and mTOR (mammalian target of rapamycin)-dependent LTD in layer 5 pyramidal neurons of mouse prefrontal cortex (PFC), a major dopaminergic target in the reward circuitry. This mGluR1-LTD impairment was prevented by in vivo administration of an mGluR1 positive allosteric modulator (PAM) and rescued by inhibition of dopamine D1 receptors, suggesting that impaired mGluR1 tone and excessive D1 signaling underlie this LTD deficit. Concurrently, CP-AMPARs were generated, indicated by increased sensitivity to the CP-AMPAR inhibitor Naspm and rectification of synaptic AMPAR currents, which were reversed by PAM in cocaine-exposed mice. Finally, these CP-AMPARs mediate an abnormal spike-timing-dependent long-term potentiation enabled by cocaine exposure. Our findings reveal a mechanism by which cocaine impairs LTD and remodels synaptic AMPARs to influence Hebbian plasticity in the PFC. Failure to undergo LTD may prevent the reversal of drug-potentiated brain circuits to their baseline states, perpetuating addictive behaviors.HIGHLIGHTSA mGluR1- and mTOR-dependent LTD is present in the mouse medial prefrontal cortex.Repeated cocaine exposure in vivo temporally but completely abolishes prefrontal mGluR1-LTD.Impaired mGluR1 function and excessive D1 DA signaling likely underlie cocaine impairment of mGluR1-LTD.Ca2+-permeable AMPA receptors are generated by cocaine exposure, likely resulting from mGluR1-LTD impairment, and contribute to a cocaine-induced extended spike timing LTP.

Intrinsic electric activities of neurons play important roles in establishing and refining neural circuits during development. However, how the underlying ionic currents undergo postembryonic reorganizations remains largely unknown. Using acutely dissociated neurons from larval, pupal, and adult Drosophila brains, we show drastic re-assemblies and compensatory regulations of voltage-gated (IKv) and Ca2+-activated (IK(Ca)) K+ currents during postembryonic development. Larval and adult neurons displayed prominent fast inactivating IKv, mediated by the Shaker (Sh) channel to a large extent, while in the same neurons IK(Ca) was far smaller in amplitude. In contrast, pupal neurons were characterized by large sustained IKv and prominent IK(Ca), encoded predominantly by the slowpoke (slo) gene. Surprisingly, deletion of Sh in the ShM null mutant removed inactivating, transient IKv from large portions of neurons at all stages. Interestingly, elimination of Sh currents was accompanied by upregulation of non-Sh transient IKv. In comparison, the slo1 mutation abolished the vast majority of IK(Ca), particularly at the pupal stage. Strikingly, the deficiency of IK(Ca) in slo pupae was compensated by the transient component of IKv mediated by Sh channels. Thus, IK(Ca) appears to play critical roles in pupal development and its absence induces functional compensations from a specific transient IKv current. While mutants lacking either Sh or slo currents survived normally, Sh;; slo double mutants deficient in both failed to survive through pupal metamorphosis. Together, our data highlight significant reorganizations and homeostatic compensations of K+ currents during postembryonic development and uncover previously unrecognized roles for Sh and slo in this plastic process.

Cholinergic dysfunction contributes to cognitive deficits associated with various neuropsychiatric disorders, including schizophrenia. The atypical antipsychotic clozapine improves cognitive function in patients with schizophrenia, possibly through modulation of the cholinergic system. However, little is known about specifics of the underlying mechanisms. In this study, we investigated the acute and chronic effects of clozapine on cholinergic synaptic transmission in cultured superior cervical ganglion (SCG) neurons. Spontaneous excitatory postsynaptic currents (sEPSCs) were readily detected in this preparation and were reversibly inhibited by the nicotinic receptor antagonist d-tubocurarine, confirming that the synaptic responses were primarily mediated by nicotinic receptors. Bath application of clozapine at therapeutic concentrations rapidly and reversely inhibited both the amplitude and frequency of sEPSCs in a concentration dependent manner, without changing either rise or decay time, suggesting that clozapine effects have both presynaptic and postsynaptic origins. The acute effects of clozapine on sEPSCs were recapitulated by chronic treatment of SCG cultures with similar concentrations of clozapine, as clozapine treatment for four days reduced the frequency and amplitude of sEPSCs without affecting their kinetics. Cell survival analysis indicated that SCG neuron cell counts after chronic clozapine treatment were comparable to the control group. These results demonstrate that therapeutic concentrations of clozapine suppress nicotinic synaptic transmission in SCG cholinergic synapses, a simple in vitro preparation of cholinergic transmission.