Hyperpolarization Induces a Long-Term Increase in the Spontaneous Firing Rate of Cerebellar Golgi Cells

Abstract

Golgi cells (GoCs) are inhibitory interneurons that influence the cerebellar cortical response to sensory input by regulating the excitability of the granule cell layer. While GoC inhibition is essential for normal motor coordination, little is known about the circuit dynamics that govern the activity of these cells. In particular, while GoC spontaneous spiking influences the extent of inhibition and gain throughout the granule cell layer, it is not known whether this spontaneous activity can be modulated in a long-term manner. Here we describe a form of long-term plasticity that regulates the spontaneous firing rate of GoCs in the rat cerebellar cortex. We find that membrane hyperpolarization, either by mGluR2 activation of potassium channels, or by somatic current injection, induces a long-lasting increase in GoC spontaneous firing. This spike rate plasticity appears to result from a strong reduction in the spike afterhyperpolarization (AHP). Pharmacological manipulations suggest the involvement of calcium-calmodulin dependent kinase II (CaMKII) and calcium-activated potassium channels in mediating these firing rate increases. As a consequence of this plasticity, GoC spontaneous spiking is selectively enhanced, but the gain of evoked spiking is unaffected. Hence this plasticity is well-suited for selectively regulating the tonic output of GoCs rather than their sensory-evoked responses.

Inverse Relationship between Basal Pacemaker Neuron Activity and Aversive Long-Term Memory Formation in Lymnaea stagnalis

“…The rules of plasticity in spontaneously active neurons may differ significantly from those in quiescent neurons (Nelson et al, 2003, 2005; Pugh and Raman, 2006, 2008; Hull et al, 2013). As spontaneously active neurons play key roles in motor and reward learning (Nelson et al, 2003, 2005; Pugh and Raman, 2008, 2009; Rueda-Orozco et al, 2009; Mure et al, 2012; Hull et al, 2013; Creed et al, 2014; Ranaldi, 2014; Weiss et al, 2014), better understanding of the full complement of plasticity mechanisms in the brain can have far-reaching impacts on addressing motor disorders and addiction.…”

“…As spontaneously active neurons play key roles in motor and reward learning (Nelson et al, 2003, 2005; Pugh and Raman, 2008, 2009; Rueda-Orozco et al, 2009; Mure et al, 2012; Hull et al, 2013; Creed et al, 2014; Ranaldi, 2014; Weiss et al, 2014), better understanding of the full complement of plasticity mechanisms in the brain can have far-reaching impacts on addressing motor disorders and addiction. This study examined the role of basal neuronal activity of spontaneously active neurons in inhibition-induced memory formation.…”

“…Due to the high levels of resting activity, spontaneously active neurons possess several distinct biophysical properties, including higher intracellular Ca 2+ levels (Muri and Knöpfel, 1994) and enhanced activation of Ca 2+ -dependent signaling molecules such as Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) (Nelson et al, 2003, 2005). Accordingly, instead of excitation, synaptic inhibition is found to be a common trigger for neural plasticity in spontaneously active neurons in the cerebellum (Nelson et al, 2003, 2005; Pugh and Raman, 2008, 2009; Hull et al, 2013) and striatum (Rueda-Orozco et al, 2009) in motor learning and the ventral tegmentum area, and subthalamic nucleus in reward- and drug-related learning (Mure et al, 2012; Creed et al, 2014; Ranaldi, 2014; Weiss et al, 2014). In the cerebellar vestibular nucleus (Nelson et al, 2003, 2005) and Golgi neurons (Hull et al, 2013), reduction of tonically elevated CaMKII activity by synaptic inhibition induces persistent enhancement in firing activity.…”

“…Accordingly, instead of excitation, synaptic inhibition is found to be a common trigger for neural plasticity in spontaneously active neurons in the cerebellum (Nelson et al, 2003, 2005; Pugh and Raman, 2008, 2009; Hull et al, 2013) and striatum (Rueda-Orozco et al, 2009) in motor learning and the ventral tegmentum area, and subthalamic nucleus in reward- and drug-related learning (Mure et al, 2012; Creed et al, 2014; Ranaldi, 2014; Weiss et al, 2014). In the cerebellar vestibular nucleus (Nelson et al, 2003, 2005) and Golgi neurons (Hull et al, 2013), reduction of tonically elevated CaMKII activity by synaptic inhibition induces persistent enhancement in firing activity. In cerebellar nuclear neurons, synaptic plasticity is triggered by the post-inhibitory rebound depolarization following synaptic inhibition from Purkinje neurons (Pugh and Raman, 2006, 2008).…”

BK Channels Are Required for Multisensory Plasticity in the Oculomotor System

“…An intriguing candidate cellular mechanism of plasticity in the oculomotor system is firing rate potentiation (FRP), in which repeated inhibition of tonically firing neurons results in long-lasting increases in intrinsic excitability via CamKII-dependent reductions in BK calcium-activated potassium currents (Nelson 2003, 2005; Hull 2013). MVN neurons fire spontaneously at high rates in vivo; their firing derives from a combination of strong excitatory drive from spontaneously firing vestibular nerve afferents, synaptic inhibition from cerebellar Purkinje cells and local circuit neurons, and intrinsic pacemaking currents (Lin and Carpenter, 1993; Gittis et al, 2007).…”