Biology subjects

Candler, C. T.

Publications and source records attributed to Candler, C. T..

3 recordsLinked to original sources

bioRxiv2026

Glutamatergic synaptic inhibition through group II mGluR-mediated suppression of the sodium leak channel NALCN

The sodium leak channel NALCN regulates resting membrane potential and spontaneous firing in neurons and can be modulated by G-protein coupled receptors (GPCRs). Whether metabotropic glutamate receptors (mGluRs) modulate NALCN is unknown and would represent a novel mechanism through which glutamate could affect neuronal excitability. Here we examine NALCN function and modulation by mGluRs in cerebellar unipolar brush cells (UBCs) in mouse brain slices. Activation of group II mGluRs inhibited the NALCN current through a G protein-dependent mechanism, as the effect was abolished by intracellular GDP-{beta}-S and by NALCN deletion. The OFF UBC subtype that is inhibited by glutamate had a larger NALCN current than the ON UBC subtype that is excited by glutamate. OFF UBCs also had a tonic NALCN current that was absent in ON UBCs. Genetic deletion of NALCN converted the regular spontaneous firing pattern of OFF UBCs, to an irregular pattern similar to that of ON UBCs, suggesting that a tonic NALCN current may be a general mechanism to promote regular firing. Additionally, we identify the presence of group III mGluRs in OFF UBCs and GABA-B receptors in ON UBCs and show that neither inhibit NALCN, demonstrating that different GPCRs engage distinct downstream ion channels. These findings identify a previously unrecognized form of glutamatergic synaptic inhibition that is selectively initiated by group II mGluRs, but not other Gi/o-coupled GPCRs, within the same neurons.

neuroscience↗

bioRxiv2023

A system of feed-forward cerebellar circuits that extend and diversify sensory signaling

Sensory signals are processed by the cerebellum to coordinate movements. Numerous cerebellar functions are thought to require the maintenance of a sensory representation that extends beyond the input signal. Granule cells receive sensory input, but they do not prolong the signal and are thus unlikely to maintain a sensory representation for much longer than the inputs themselves. Unipolar brush cells (UBCs) are excitatory interneurons that project to granule cells and transform sensory input into prolonged increases or decreases in firing, depending on their ON or OFF UBC subtype. Further extension and diversification of the input signal could be produced by UBCs that project to one another, but whether this circuitry exists is unclear. Here we test whether UBCs innervate one another and explore how these small networks of UBCs could transform spiking patterns. We characterized two transgenic mouse lines electrophysiologically and immunohistochemically to confirm that they label ON and OFF UBC subtypes and crossed them together, revealing that ON and OFF UBCs innervate one another. A Brainbow reporter was used to label UBCs of the same ON or OFF subtype with different fluorescent proteins, which showed that UBCs innervate their own subtypes as well. Computational models predict that these feed-forward networks of UBCs extend the length of bursts or pauses and introduce delays--transformations that may be necessary for cerebellar functions from modulation of eye movements to adaptive learning across time scales. SIGNIFICANCE STATEMENTThe cerebellum is essential for the accurate performance of behaviors ranging in complexity from stabilizing an image on the retina to playing a piano or performing a gymnastics routine. Cerebellar dysfunction disrupts the ability to produce smooth movements and leads to a disorder called ataxia. Damage to the vestibular cerebellum occurs in various disorders including medulloblastoma and leads to nystagmus, involuntary movements of the eyes that prevent normal vision. Treating disorders of motor control such as nystagmus, requires a better understanding of how representations of movements are maintained in the firing patterns of neurons in the cerebellar circuit. Here we use transgenic mice to label a type of neuron called the unipolar brush cell and revealed that these cells innervate one another and are likely to increase the length and diversity of spiking patterns in the cerebellum. These transformations may be necessary for numerous functions from controlling eye movements to learning new behaviors.

neuroscience↗

bioRxiv2021

Correction of amblyopia in cats and mice after the critical period

Monocular deprivation early in development causes amblyopia, a severe visual impairment. Prognosis is poor if therapy is initiated after an early critical period. However, clinical observations have shown that recovery from amblyopia can occur later in life when the non-deprived (fellow) eye is removed. The traditional interpretation of this finding is that vision is improved by relieving interocular suppression in primary visual cortex. However, an alternative explanation is that elimination of activity in the fellow eye establishes conditions in visual cortex that enable the weak connections from the amblyopic eye to gain strength. Here we show in cats and mice that temporary inactivation of the fellow eye is sufficient to promote a full and enduring recovery from amblyopia at ages when conventional treatments fail. Thus, connections serving the amblyopic eye are capable of substantial plasticity beyond the critical period, and this potential is unleashed by reversibly silencing the fellow eye.

neuroscience↗