Biology subjects

Valtcheva, S.

Publications and source records attributed to Valtcheva, S..

3 recordsLinked to original sources

bioRxiv2024

Endocytic adaptor AP-2 maintains Purkinje cell function by balancing cerebellar parallel and climbing fiber synapses

The selective loss of cerebellar Purkinje cells is a hallmark of various neurodegenerative movement disorders, yet the precise mechanism driving their degeneration remains enigmatic. Here, we show that the endocytic adaptor protein complex 2 (AP-2) is essential for the survival of Purkinje cells. Employing a multidisciplinary approach encompassing mouse genetics, viral tracing, ex vivo calcium imaging, and kinematic analysis, we demonstrate that mice lacking the {micro}-subunit of AP-2 in cerebellar Purkinje cells exhibit early-onset ataxia associated with progressive Purkinje cell degeneration. Importantly, we uncover that synaptic input dysfunctions, characterized by a predominance of parallel fiber (PF) over climbing fiber (CF) synapses, precede Purkinje cell loss. Mechanistically, we find that AP-2 localizes to Purkinje cell dendrites, where it interacts with the PF synapse-enriched protein GRID2IP. The loss of AP-2 results in proteasome-dependent degradation of GRID2IP and accumulation of the glutamate {delta}2 receptor (GLUR{delta}2) in distal Purkinje cell dendrites, leading to an excess of PF synapses while CF synapses are drastically reduced. The overrepresentation of PF synaptic input induces Purkinje cell hyperexcitation, which can be alleviated by enhancing synaptic glutamate clearance using the antibiotic ceftriaxone. Our findings demonstrate the critical role of AP-2 in preventing motor gait dysfunctions by regulating GRID2IP levels in Purkinje cells, thereby preserving the equilibrium of PF and CF synaptic inputs in a cell-autonomous manner.

neuroscience↗

bioRxiv2021

Neural circuitry for maternal oxytocin release induced by infant cries

Oxytocin is a neuropeptide important for maternal physiology and childcare, including parturition and milk ejection during nursing1-8. Suckling triggers oxytocin release, but other sensory cues- specifically infant cries- can elevate oxytocin levels in new human mothers9-11 indicating that cries can activate hypothalamic oxytocin neurons. Here we describe a neural circuit routing auditory information about infant vocalizations to mouse oxytocin neurons. We performed in vivo electrophysiological recordings and photometry from identified oxytocin neurons in awake maternal mice presented with pup calls. We found that oxytocin neurons responded to pup vocalizations, but not pure tones, via input from the posterior intralaminar thalamus, and repetitive thalamic stimulation induced lasting disinhibition of oxytocin neurons. This circuit gates central oxytocin release and maternal behavior in response to calls, providing a mechanism for the integration of sensory cues from the offspring in maternal endocrine networks to ensure modulation of brain state for efficient parenting.

neuroscience↗

bioRxiv2020

Innate sensitivity and plastic mechanisms in auditory cortex for reliable maternal behavior

Infant cries evoke powerful responses in parents1-4. To what extent are parental animals innately sensitive to neonatal vocalizations, or might instead learn about key vocal cues for appropriate parenting responses? In mice, naive virgins do not recognize the meaning of pup distress calls, but begin to retrieve pups to the nest following cohousing with a mother and litter5-8. These isolation calls can be variable, requiring co-caring virgins to generalize across features for reliable retrieval9, 10. Here, using behavioral studies combined with two-photon imaging and whole-cell recordings, we show that the onset of maternal behavior in mice results from the interaction between innate sensitivities and experience-dependent processes. We found that pup calls with inter-syllable intervals (ISIs) ranging from 75 to 375 ms elicited pup retrieval, and experienced auditory cortex generalized across these ISIs. In contrast, naive cortex was narrowly tuned to the most common or prototypical ISIs due to enhanced short-term depression of inhibitory inputs. Behavioral testing revealed that naive virgins were also more sensitive to prototypical calls than calls at other rates. Inhibitory and excitatory spiking and synaptic responses were initially mismatched in naive cortex, with untuned inhibition and overly-narrow excitation. Monitoring neuronal populations over cohousing revealed that excitatory neuronal responses broadened to represent a wide range of ISIs, while inhibitory neurons sharpened to form a perceptual boundary. Finally, we presented synthetic calls during cohousing and observed that neural and behavioral responses adjusted to match these statistics. Using inhibitory optogenetics, we found that auditory cortical activity was required to learn about specific features, whereas the oxytocinergic system was generally recruited for retrieval learning and plasticity in temporal tuning. Neuroplastic mechanisms therefore build on an innate sensitivity in the auditory cortex, enabling rapid plasticity for reliable parenting behavior.

neuroscience↗