In addition to its well-studied role in motor control, the cerebellum sends outputs to a variety of non-motor brain regions including the prefrontal cortex and limbic system, and thus plays an important role in emotional regulation. One model for emotional learning and memory is Pavlovianfearconditioning, a form of associative fear memory. The cerebellum is required for the formation of this type of associative fear memory. Using this paradigm, our long-term goal is to identify the cerebellar neural correlates of emotional memory and to understand how psychological stress enhances associative learning. Over the last ten years, our research has evolved from the study of synaptic plasticity in brain slices to examining experience-induced changes in cerebellar network activity, and ultimately how neural plasticity alters animal behavior.
Emotional stress regulates glutamate receptor gene expression. Changes in emotional state are known to alter neuronal excitability and can modify learning and memory formation. In a recent study we have shown that a single exposure to a fear-inducing stimulus induces a long-lasting increase in the transcription of the GluR2 subunit of the AMPA-type glutamate receptor in cerebellar inhibitory interneurons (Liu et al, 2010). This reduces the AMPA receptor Ca2+ permeability and alters synaptic efficacy.
Fear memories and synaptic plasticity. Cerebellar lobule V/VI is critically involved in the consolidation of associative fear conditioning. We use DREADD technologies to selectively activate and suppress the activity of different types of cerebellar neurons to determine the role of these neurons in the formation of associative fear memory. We have identified several forms of cerebellar neuronal plasticity following fear conditioning (manuscripts submitted). We are particular interested in understanding the molecular mechanism(s) underlying learning-induced alterations in endocannabinoid signaling, AMPA receptor subtype expression, and lasting changes in the intrinsic excitability of cerebellar interneurons. In addition, we have started to determine the effect of these forms of neural plasticity on the activity of cerebellar neuronal circuits.
Topological Regulation of Synaptic AMPA Receptor Expression. In recent work we have demonstrated that action potential activity changes the expression of CPEB3 (an RNA binding protein) which interacts with GluA2 mRNA and controls GluA2 protein synthesis. This process is critically involved in establishing a GluA2 gradient along the dendrites of interneurons in the molecular layer of the cerebellum (Savtchouk et al, Cell Reports, 2016; Bender et al, Neuropharmacology, 2015). These studies demonstrate a cell-autonomous modulation of synaptic AMPAR expression that is controlled by postsynaptic AP firing.
Savtchouk I, Sun L, Bender C, Yang Q, Gasparini S and Liu S.J.* (2016) Topostatic regulation of synaptic AMPA receptor expression by the RNA-binding protein, CPEB3. Cell Reports 17(1):86-103.
Dubois, CJ, Lachamp, PM, Sun, L, Mishina, M and Liu, S.J.* (2016) Presynaptic GluN2D receptors detect glutamate spillover and regulate cerebellar GABA release. J. Neurophysiol. 115(1):271-85
Savtchouk, I. and Liu S.J.* (2011) Remodeling of synaptic AMPA receptor subtype alters the probability and pattern of action potential firing. J. Neurosci. 31:501-511.
Liu, Y, Formisano, L, Takayasu, Y, Savtchouk I, Szabó G, Zukin, R.S. and Liu, S.J.* (2010) A single fear-inducing stimulus induces a transcription-dependent switch in synaptic AMPAR phenotype. Nature Neuroscience. 13:223-31.
Lachamp, P. M., Liu, Y and Liu, S.J.* (2009) Glutamatergic modulation of cerebellar interneuron activity is mediated by an enhancement of GABA release and requires PKA/RIM1a-signaling. J. Neurosci. 29:381-92.
Bender C, Yang Q, Sun L and Liu S.J.* (2016) NH125 reduces the level of CPEB3, an RNA binding protein, to promote synaptic GluA2 expression. Neuropharmacology. 101:531-7.
Maroteaux M and Liu S.J.* (2016) Alteration of AMPA receptor-mediated synaptic transmission by Alexa Fluor 488 and 594 in cerebellar stellate cells. eNeuro. 3(3) 0109-15
Dubois, C.J., Ramamoorthy, P., Whim, M.D. and Liu, S.J.* (2012) Activation of NPY type 5 receptors induces a long-lasting increase in spontaneous GABA release from cerebellar stellate cells. J. Neurophysiol. 107(6):1655-65.
Liu, S.J.* and Savtchouk, I. (2012) Ca-permeable AMPA receptors switch allegiances: mechanisms and consequences. J. Physiol. 590:13-20.
Liu, Y, Savtchouk, I, Acharjee, S and Liu, S.J.* (2011) Inhibition of Ca2+-activated large-conductance K+ channel activity alters synaptic AMPA receptor phenotype in mouse cerebellar stellate cells. J. Neurophysiol. 106:144-153.
Liu, S.J.*, Lachamp P, Liu Y, Savtchouk I and Sun L. (2008) Long-term synaptic plasticity in cerebellar stellate cells. The Cerebellum. 7:559-62.
Sun, L and Liu, S.J.* (2007) Activation of extrasynaptic NMDA receptors induces a PKC-dependent switch in AMPA receptor subtypes in mouse cerebellar stellate cells. J. Physiol. 583:537-553.
Liu, S. J.(2007) Biphasic Modulation of GABA Release from stellate cells by glutamatergic receptor subtypes. J. Neurophysiol. 98:550-556.
Liu S.J. and Zukin RS (2007) Ca2+-permeable AMPA receptors in synaptic plasticity and neuronal death. Trends in Neurosci. 30:126-34.
Liu S.J.* and Lachamp P (2006) The activation of excitatory glutamate receptors evokes a long-lasting increase in the release of GABA from cerebellar stellate cells. J Neurosci. 26:9332-9.
Liu S.J. and Cull-Candy S (2005) Subunit interaction with PICK and GRIP controls Ca2+-permeability of AMPARs at cerebellar synapses. Nature Neurosci. 8:768-775.
Liu S.Q. and Kaczmarek LK. (2004) Aminoglycosides block the Kv3.1 potassium channel and reduce the ability of inferior colliculus neurons to fire at high frequencies. J Neurobiol. 62:439-452.
Liu, S.J. and S. G. Cull-Candy. (2002) Activity-dependent change in AMPA receptor properties in cerebellar stellate cells. J. Neurosci. 22: 3881-9.
Liu, S.J. and S. G. Cull-Candy (2000) Synaptic activity at calcium-permeable AMPA receptors induces a switch in receptor subtype. Nature 405: 454-458.
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Liu, S. J. and Dubois, C. (2016) Stellate cells. In Essentials of Cerebellum and Cerebellar Disorders