Cerebellar Learning
My doctoral dissertation involved understanding how proteomic regulation of potassium ion channels by PKM-ζ may impact cerebellar learning and memory. More specifically, we are investigating the role of a special kinase, PKM-ζ (PKM-Zeta), in modulating cerebellar-dependent learning through regulation of Kv1.2 (a voltage-gated potassium ion channel).
I, as well as countless others, are fascinated with PKM-ζ because it has long been implicated in a hippocampal cellular correlate of learning, long-term potentiation (LTP), through its regulation of hippocampal AMPA receptors (Ling et al., 2002; Yao et al., 2008). Disruption of PKM-ζ with Zeta-inhibitory peptide (ZIP) can irreversibly disrupt hippocampal memory that has been maintained for many weeks (Hernandez et al., 2003).
Despite being highly expressed in the cerebellum (Oster et al., 2004), no studies have examined how regulation of cerebellar PKM-ζ may affect cerebellar-dependent learning and memory. We have shown for the first time that infusion of ZIP in the lobulus simplex of the cerebellum can significantly disrupt delay eye-blink conditioning (EBC) in rats, a form of cerebellar-dependent learning (Chihabi et al., 2016). Interestingly, several studies have shown that PKC-ζ can co-immunoprecipitate with and phosphorylate a β subunit that associates with cerebellar Kv1.2 (Gong et al., 1999; Croci et al., 2003). Kv1.2 is highly expressed in cerebellar basket cell axon terminals and Purkinje cell dendrites and our lab has shown that Kv1.2 is important for cerebellar EBC in rats (Williams et al., 2012; Fuchs et al., 2014). Therefore we hypothesized that PKM-ζ may have regulatory effects on voltage-gated potassium channel alpha-subunit 1.2 (Kv1.2). We have recently demonstrated that PKM-ζ can significantly reduce Kv1.2 surface expression in HEK 293 cells (Chihabi et al., in preparation) and are working towards mapping out the mechanism of action. Our work is now pioneering the involvement of PKM-ζ in cerebellar circuitry.
Publications:
Chihabi K, Morielli AD, Green JT (2016). Intracerebellar infusion of the protein kinase Mzeta (PKMζ) inhibitor ZIP disrupts eyeblink classical conditioning. Behavioral Neuroscience, 130(6): 563–571.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014731/
https://library.uvm.edu/dissertations/?search_type=item&bid=4018840
I, as well as countless others, are fascinated with PKM-ζ because it has long been implicated in a hippocampal cellular correlate of learning, long-term potentiation (LTP), through its regulation of hippocampal AMPA receptors (Ling et al., 2002; Yao et al., 2008). Disruption of PKM-ζ with Zeta-inhibitory peptide (ZIP) can irreversibly disrupt hippocampal memory that has been maintained for many weeks (Hernandez et al., 2003).
Despite being highly expressed in the cerebellum (Oster et al., 2004), no studies have examined how regulation of cerebellar PKM-ζ may affect cerebellar-dependent learning and memory. We have shown for the first time that infusion of ZIP in the lobulus simplex of the cerebellum can significantly disrupt delay eye-blink conditioning (EBC) in rats, a form of cerebellar-dependent learning (Chihabi et al., 2016). Interestingly, several studies have shown that PKC-ζ can co-immunoprecipitate with and phosphorylate a β subunit that associates with cerebellar Kv1.2 (Gong et al., 1999; Croci et al., 2003). Kv1.2 is highly expressed in cerebellar basket cell axon terminals and Purkinje cell dendrites and our lab has shown that Kv1.2 is important for cerebellar EBC in rats (Williams et al., 2012; Fuchs et al., 2014). Therefore we hypothesized that PKM-ζ may have regulatory effects on voltage-gated potassium channel alpha-subunit 1.2 (Kv1.2). We have recently demonstrated that PKM-ζ can significantly reduce Kv1.2 surface expression in HEK 293 cells (Chihabi et al., in preparation) and are working towards mapping out the mechanism of action. Our work is now pioneering the involvement of PKM-ζ in cerebellar circuitry.
Publications:
Chihabi K, Morielli AD, Green JT (2016). Intracerebellar infusion of the protein kinase Mzeta (PKMζ) inhibitor ZIP disrupts eyeblink classical conditioning. Behavioral Neuroscience, 130(6): 563–571.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014731/
https://library.uvm.edu/dissertations/?search_type=item&bid=4018840