Biology subjects

Notter, T.

Publications and source records attributed to Notter, T..

3 recordsLinked to original sources

bioRxiv2026

Developmental Trajectory of Synaptic Remodeling in the Mouse Prefrontal Cortex

The prefrontal cortex (PFC) is a heteromodal association area critical for higher-order cognitive functions. Its protracted maturation extends through adolescence into early adulthood, a period characterized by extensive remodeling of neuronal networks and synaptic architecture. This heightened plasticity supports the refinement of prefrontal circuits necessary to meet the evolving cognitive and behavioral demands of this developmental transition. However, the extended maturation window also increases vulnerability to environmental perturbations, which can lead to lasting synaptic and cognitive impairments. Despite widespread use of developmental disruption models during adolescence, a systematic characterization of synaptic dynamics during normal PFC maturation is lacking. Here, we combined longitudinal in vivo two-photon imaging of dendritic spines with cross-sectional quantification of excitatory and inhibitory synapses, and microglia-mediated synaptic engulfment, in mice from juvenile to adult stages. This integrated approach provides a comprehensive reference atlas of normal prefrontal synaptic maturation, offering a framework for interpreting alterations to synapses in models of developmental disturbance.

neuroscience↗

bioRxiv2026

Adolescent Astrocyte Dysregulation Impairs Prefrontal Interneuron Maturation and Adult Cognition

The prefrontal cortex (PFC), a brain region critical for executive and cognitive functions, is characterized by its protracted maturation extending through adolescence until early adulthood. During adolescence, the PFC undergoes substantial rearrangements, creating a window of heightened plasticity allowing experience-dependent refinement of neural networks. While this extended plasticity supports the development of higher-order cognitive functions, it also confers increased vulnerability to environmental and biological perturbations that can disrupt circuit development and contribute to cognitive and behavioral impairments relevant to psychiatric disorders. Astrocytes are central regulators of brain homeostasis and actively participate in developmental processes that shape postnatal brain maturation. Although astrocyte dysfunction has been increasingly linked to psychiatric pathophysiology, it remains unknown whether aberrant astrocyte activity can directly influence PFC development and cognitive maturation. Here, using selective modulation of astrocyte activity during defined developmental windows in the PFC, we show that abnormal astrocyte activity during adolescence induces transient synaptic loss through enhanced microglial phagocytosis, produces long-lasting alterations in fast-spiking parvalbumin (PV) interneurons, and results in persistent deficits in PFC-dependent behaviors. Together, these findings provide causal evidence that disrupted astrocyte function during adolescent PFC maturation can lead to persistent neuronal and cognitive deficits with relevance to major psychiatric disorders.

neuroscience↗

bioRxiv2024

Overactivation of prefrontal astrocytes impairs cognition through the metabolic pathway of central kynurenines

Astrocyte dysfunctions have long been implicated in psychiatric and cognitive disorders, yet the precise mechanisms underlying this association remain elusive. Here, we show that chemogenetic activation of prefrontal astrocytes in mice impairs short-term memory and sensorimotor gating and attenuates the activation of parvalbumin (PV) interneurons in the prefrontal cortex. These alterations are accompanied by increases in prefrontal levels of kynurenic acid (KYNA), a key metabolite of the kynurenine (KYN) pathway, known to be produced by astrocytes, which serves as an endogenous antagonist of NMDA receptors. Pharmacological inhibition of kynurenine aminotransferase II, the key enzyme mediating the transamination of KYN to KYNA, reinstates the astrocyte-mediated impairments in short-term memory and sensorimotor gating, and normalizes the deficits in prefrontal PV interneuron activation. Our study identifies a mechanistic link between overactivation of prefrontal astrocytes, increased production of KYNA, and cognitive as well as cellular dysfunctions involved in major psychiatric disorders and beyond.

neuroscience↗