Victor Z. Han

Bidirectional plasticity in the primate inferior olive induced by chronic ethanol intoxication and sustained abstinence

The brain adapts to chronic ethanol intoxication by altering synaptic and ion-channel function to increase excitability, a homeostatic counterbalance to inhibition by alcohol. Delirium tremens occurs when those adaptations are unmasked during withdrawal, but little is known about whether the primate brain returns to normal with repeated bouts of ethanol abuse and abstinence. Here, we show a form of bidirectional plasticity of pacemaking currents induced by chronic heavy drinking within the inferior olive of cynomolgus monkeys. Intracellular recordings of inferior olive neurons demonstrated that ethanol inhibited the tail current triggered by release from hyperpolarization (Itail). Both the slow deactivation of hyperpolarization-activated cyclic nucleotide-gated channels conducting the hyperpolarization-activated inward current and the activation of Cav3.1 channels conducting the T-type calcium current (IT) contributed to Itail, but ethanol inhibited only the IT component of Itail. Recordings of inferior olive neurons obtained from chronically intoxicated monkeys revealed a significant up-regulation in Itail that was induced by 1 y of daily ethanol self-administration. The up-regulation was caused by a specific increase in IT which (i) greatly increased neurons’ susceptibility for rebound excitation following hyperpolarization and (ii) may have accounted for intention tremors observed during ethanol withdrawal. In another set of monkeys, sustained abstinence produced the opposite effects: (i) a reduction in rebound excitability and (ii) a down-regulation of Itail caused by the down-regulation of both the hyperpolarization-activated inward current and IT. Bidirectional plasticity of two hyperpolarization-sensitive currents following chronic ethanol abuse and abstinence may underlie persistent brain dysfunction in primates and be a target for therapy.

Synaptic Plasticity and Calcium Signaling in Purkinje Cells of the Central Cerebellar Lobes of Mormyrid Fish

Climbing fiber (CF)-evoked calcium transients play a key role in plasticity at parallel fiber (PF) to Purkinje cell synapses in the mammalian cerebellum. Whereas PF activation alone causes long-term potentiation (LTP), coactivation of the heterosynaptic CF input, which evokes large dendritic calcium transients, induces long-term depression (LTD). This unique type of heterosynaptic interaction is a hallmark feature of synaptic plasticity in mammalian Purkinje cells. Purkinje cells in the cerebellum of mormyrid electric fish are characterized by a different architecture of their dendritic trees and by a more pronounced separation of CF and PF synaptic contact sites. We therefore examined the conditions for bidirectional plasticity at PF synapses onto Purkinje cells in the mormyrid cerebellum in vitro. PF stimulation at elevated frequencies induces LTP, whereas LTD results from PF stimulation at enhanced intensities and depends on dendritic calcium influx and metabotropic glutamate receptor type 1 activation. LTD can also be observed after pairing of low intensity PF stimulation with CF stimulation. Using a combination of whole-cell patch-clamp recordings and fluorometric calcium imaging, we characterized calcium transients in Purkinje cell dendrites. CF activation elicits calcium transients not only within the CF input territory (smooth proximal dendrites) but also within the PF input territory (spiny palisade dendrites). Paired PF and CF activation elicits larger calcium transients than stimulation of either input alone. A major source for dendritic calcium signaling is provided by P/Q-type calcium channels. Our data show that despite the spatial separation between the two inputs CF activity facilitates LTD induction at PF synapses.

Functional circuitry of a unique cerebellar specialization: the valvula cerebelli of a mormyrid fish.

The valvula cerebelli of the mormyrid electric fish is a useful site for the study of cerebellar function. The valvula forms a part of the electrosensory-electromotor system of this fish, a system that offers many possibilities for the study of sensory-motor integration. The valvula also has a number of histological features not present in mammals which facilitate investigation of cerebellar circuitry and its plasticity. This initial study characterizes the basic physiology and pharmacology of cells in the valvula using an in vitro slice preparation. Intrinsic properties and synaptic responses of Purkinje cells and other cell types were examined. We found that Purkinje cells fire a small narrow Na(+) spike and a large broad Ca(2+) spike, generated in the axon initial segment and dendritic-soma region, respectively. Purkinje cells respond to parallel fiber inputs with graded excitatory postsynaptic potentials (EPSPs) and to climbing fiber inputs with all-or-none EPSPs. Efferent cells, Golgi cells, and deep stellate cells all fire a single type of large narrow spike and respond only to parallel fiber inputs. Both parallel fiber and climbing fiber responses in Purkinje cells appear to be entirely mediated by AMPA-type glutamate receptors, whereas parallel fiber responses in efferent cells and stellate cells include AMPA and NMDA components. In addition, a strong synaptic inhibition was uncovered in both Purkinje cells and efferent cells in response to the focal stimulation of parallel fibers. Dual cell recordings indicate that deep stellate cells contribute at least partially to this inhibition. We conclude that despite its unique histology, the local functional circuitry of the mormyrid valvula cerebelli is largely similar to that of the mammalian cerebellum. Thus, what is learned concerning the functioning of the mormyrid valvula cerebelli may be expected to be informative about cerebellar function in general.

Synaptic dynamics and long-term plasticity at synapses of Purkinje cells onto neighboring Purkinje cells of a mormyrid fish: A dual cell recording study

The input synapses of cerebellar Purkinje cells (PCs) have been extensively studied and much has been learned about their dynamics, plasticity and functionality. In contrast there is limited information available about PC output synapses. This study uses dual cell recording methods to investigate synaptic dynamics and plasticity at individual PC synapses onto neighboring PCs in in vitro preparations of the mormyrid cerebellum. This synaptic connectivity may be strong or weak. For strong connections, inhibitory postsynaptic potentials (IPSPs) or currents (IPSCs) are synchronized with the action potentials of the presynaptic cell. For weak connections, however, the pre- and postsynaptic potentials are no longer synchronized, and presynaptic burst firing at intraburst rates of ∼50 Hz or higher is required to reliably induce the postsynaptic inhibition. A depression of this postsynaptic inhibition was observed for both types of connectivity following repeated presynaptic bursts, which was subsequently largely reversed following pairings of the presynaptic burst-induced IPSPs/IPSCs with evoked burst firing of the postsynaptic cell. Moreover, the original postsynaptic depression was found to be either augmented or reversed depending on the temporal order of each pair of additional pre- and postsynaptic cell activations, hence demonstrating a reversible and spike timing-dependent plasticity (STDP) at this synapse.

Cell type-specific plasticity at parallel fiber synapses onto Purkinje cells in the posterior caudal lobe of the mormyrid fish cerebellum

It has been demonstrated that there are two morphological subtypes of Purkinje cells (PCs)-fan-shaped Purkinje cells (fPCs) and multipolar Purkinje cells (mPCs)-in the posterior caudal lobe of the mormyrid fish cerebellum, but whether these cell types are also functionally distinct is unknown. Here, we have used electrophysiological and pharmacological tools in a slice preparation to demonstrate that pairing parallel fiber (PF) and climbing fiber (CF) inputs at a low frequency induces long-term depression (LTD) in fPCs but long-term potentiation (LTP) in mPCs. The induction of plasticity in both cell types required postsynaptic Ca2+ and type 1α metabotropic glutamate receptors. However, the LTD in fPCs was inducted via a calcium/calmodulin-dependent protein kinase II cascade, whereas LTP induction in mPCs required calcineurin. Moreover, the LTD in fPCs and LTP in mPCs were accompanied by changes to the corresponding paired-pulse ratios and their coefficients of variation, suggesting presynaptic modes of expression for the plasticity at PF terminals for both cell types. Hence, the synaptic plasticity at PF synapses onto PCs in the posterior caudal lobe of the mormyrid cerebellum is cell type specific, with both pre- and postsynaptic mechanisms contributing to its induction and expression. NEW & NOTEWORTHY Much has been learnt about the cerebellar long-term depression (LTD) in the cortex. More recent work has shown that long-term potentiation (LTP) is equally important for cerebellar motor learning. Here we report for the first time that plasticity in the mormyrid cerebellum is cell type specific, e.g., following the conventional pairing of parallel and climbing fiber inputs in an in vitro preparation leads to LTD in one Purkinje cell subtype and LTP in another.