Increased firing frequency of spontaneous action potentials in cerebellar Purkinje neurons of db/db mice results from altered auto-rhythmicity and diminished GABAergic tonic inhibition

Abstract

Abstract. The hormone leptin, by binding to hypothalamic receptors, suppresses food intake and decreases body adiposity. Leptin receptors are also widely expressed in extra-hypothalamic areas such as hippocampus, amygdala and cerebellum, where leptin modulates synaptic transmission. Here we show that a defective leptin receptor affects the electrophysiological properties of cerebellar Purkinje neurons (PNs). PNs from (db/db) mice recorded in cerebellar slices display a higher firing rate of spontaneous action potentials than PNs from wild type (WT) mice. Blockade of GABAergic tonic inhibition with bicuculline in WT mice changes the firing pattern from continuous, uninterrupted spiking into bursting firing, but bicuculline does not produce these alterations in db/db neurons, suggesting that they receive a weaker GABAergic inhibitory input. Our results also show that the intrinsic firing properties (auto-rhythmicity) of WT and db/db PNs are different. Tonic firing of PNs, the only efferent drive from the cerebellar cortex, is a persistent signal to downstream cerebellar targets. The significance of leptin modulation of PNs spontaneous firing is not known. Also, it is not clear if the increased excitability of cerebellar PNs in db/db mice results from hyperglycemia or from the lack of leptin signaling, since both conditions coexist in the db/db strain.

Ketohexokinase-dependent metabolism of cerebral endogenous fructose in microglia drives diabetes-associated cognitive dysfunction

“…The decline in the amplitude and frequency of mEPSCs was in accordance with pre-and postsynaptic deficits, which corresponded with the loss of mushroom spines (the mature "memory spine") in the hippocampus of db/db mice. In contrast, the frequency of sEPSCs was increased, which may be due to the hyperexcitability of neurons in db/db mice 34 . Increased action potential (AP) frequency and decreased threshold potential of CA1 pyramidal neurons validated our assumption.…”

“…7d-f). Due to increased neuronal excitability in db/db mice 34 , we speculated that the elevation of sEPSCs may be associated with increased AP frequency. Our results demonstrated that the AP frequency increased and the threshold potential level slightly declined in the db/db mice, whereas the parameters recovered after Khk depletion (Fig.…”

Cerebellar Nonmotor Functions – Approaches and Significance

“…Specific nonrandom connectivity patterns in interneuronal networks connected by both GABAergic chemical and electrical synaptic contacts are essential for the function of the cerebellar cortical network [26]. Defective leptin receptors affect the electrophysiological properties of cerebellar PCs in a rodent model for obesity and type-2 diabetes [27]. Motor memories are postulated to be stored in the form of long-term depression/ potentiation not only at parallel fiber synapses with PCs, but also at several other synapses mostly dependent on calcium (reviewed in [28]).…”