Biology subjects

Balmer, T. S.

Publications and source records attributed to Balmer, T. S..

6 recordsLinked to original sources

bioRxiv2026

Developmental NMDA receptor signaling regulates cerebellar unipolar brush cell number and dampens excitability

Unipolar brush cells (UBCs) are excitatory interneurons that have a characteristic dendritic brush that amplifies and extends incoming signals in the cerebellum. UBCs transform synaptic input through their ionotropic and metabotropic glutamate receptors. Differential regulation of receptor subunits is a critical developmental process, but how the expression of glutamatergic receptors changes in UBCs as they develop is unclear. NMDA-type glutamate receptors (NMDARs) are particularly important for development and plasticity. We examined the expression of NMDAR subunits during development and tested whether signaling through these receptors is necessary for the development of the elaborate dendritic structure and unusual synaptic function of UBCs. Whole-cell patch clamp recordings from UBCs in acute brain slices revealed tonic and synaptic NMDAR-mediated currents in early postnatal UBCs that decrease during development. RNAscope in situ hybridization revealed differential developmental regulation of GluN2C/D subunits. Cell-type specific constitutive NMDAR knockout had no apparent effect on dendritic brush development, but increased UBC number in adulthood, suggesting a role in programmed cell death. Both pharmacological blockade or genetic deletion of NMDARs produced a paradoxical increase in excitability, which was calcium dependent and was occluded by inhibition of calcium activated potassium channels. Thus, NMDA receptors are dispensable for migration and dendritic development but may be involved in cell death pathways. Their functional roles include synaptic signaling as well as providing a tonic calcium flux that dampens excitability in developing UBCs and may influence transformations of vestibular signals essential for smooth movements and balance.

neuroscience↗

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↗

bioRxiv2020

Incomplete removal of extracellular glutamate controls synaptic transmission and integration at a cerebellar synapse

Synapses of glutamatergic mossy fiber onto cerebellar unipolar brush cells (UBCs) generate slow excitatory (ON) or inhibitory (OFF) postsynaptic responses dependent on the complement of glutamate receptors expressed on the UBCs large dendritic brush. Using brain slice recording and computational modeling of synaptic transmission, we found that substantial glutamate is maintained in the UBC synaptic cleft, sufficient to modify spontaneous firing in OFF UBCs and tonically desensitize AMPARs of ON UBC. The source of ambient glutamate was spontaneous, spike-independent exocytosis from the mossy fiber terminal, and its level was dependent on activity of glutamate transporters EAAT1-2. Changing levels of ambient glutamate shifted the polarity of evoked synaptic responses in ON UBCs and altered the phase of responses to in vivo-like synaptic activity. Unlike classical fast synapses, receptors at the UBC synapse are virtually always exposed to a significant level of glutamate, which varies in a graded manner during transmission.

neuroscience↗

bioRxiv2019

Selective targeting of unipolar brush cell subtypes by cerebellar mossy fibers

In vestibular cerebellum, primary afferents carry signals from single vestibular end organs, whereas secondary afferents from vestibular nucleus carry integrated signals. Selective targeting of distinct mossy fibers to postsynaptic cells determines how the cerebellum processes vestibular signals. We focused on vestibular projections to ON and OFF classes of unipolar brush cells (UBCs), which transform single mossy fiber signals into long-lasting excitation or inhibition respectively, and impact the activity of ensembles of granule cells. To determine whether these contacts are indeed selective, connectivity was traced back from UBC to specific ganglion cell, hair cell and vestibular organ subtypes. We show that a specialized subset of primary afferents contacts ON UBCs, but not OFF UBCs, while secondary afferents contact both subtypes. Striking anatomical differences were observed between primary and secondary afferents, their synapses, and the UBCs they contact. Thus, each class of UBC functions to transform specific signals through distinct anatomical pathways.

neuroscience↗

bioRxiv2018

TrkB activation during a critical period mimics the protective effects of early visual experience on the stability of receptive fields in adult superior colliculus

During a critical period in postnatal development, spontaneous and evoked retinal activity shape nascent visual pathways in an adaptive fashion. Visual experience increases transcription of the neurotrophin BDNF, activating the BDNF receptor TrkB, which promotes maturation of parvalbumin (PV) positive inhibitory interneurons, a process thought to open a critical period for ocular dominance plasticity in visual cortex. Development of perineuronal nets around PV neurons limits plasticity, ending the critical period and restricting adult plasticity. Another form of critical period plasticity is receptive field (RF) refinement. Spontaneous activity alone is sufficient for spatial refinement of visual receptive fields in superior colliculus (SC) and visual cortex (V1), but visual experience during an early critical period is necessary to maintain inhibitory synapses and stabilize RFs in adulthood (Carrasco et al. 2005, 2011; Carrasco & Pallas 2006; Balmer & Pallas 2015a). We report here that deprivation-induced RF enlargement in adulthood has a behavioral consequence; it impairs fear responses to looming objects in mice and hamsters. The mechanism through which early experience protects RFs from deprivation-induced loss of inhibition in adulthood is unknown. Given that the loss of RF refinement in SC does not occur until adulthood, and that inhibitory PV neurons and perineuronal nets are rare in SC, we asked whether or not BDNF-TrkB signaling was involved. We find that early TrkB activation is necessary and sufficient to maintain visual RF refinement in adulthood, suggesting a common signaling pathway for maturation of inhibition across neuronal subtypes and locations within the visual pathway.\n\nSignificance StatementReceptive field refinement in superior colliculus (SC) differs from more commonly studied examples of critical period plasticity in visual pathways in that it does not require visual experience to occur; rather spontaneous activity is sufficient. Maintenance of refinement requires brief, early exposure to light to stabilize inhibition beyond puberty. This type of inhibitory plasticity must not depend on parvalbumin (PV)-containing GABAergic interneurons or on the formation of perineuronal nets, because these are very uncommon in SC. Nonetheless, we find that TrkB activation during a critical period can substitute for visual experience in maintaining receptive field refinement into adulthood, and that this maintenance is beneficial to visual survival behaviors. Thus, multiple types of plasticity converge on the same neurotrophin-dependent signaling cascade.

neuroscience↗