Dulla, C. | Search bioRxiv

bioRxiv2023

Traumatic brain injury disrupts state-dependent functional cortical connectivity in a mouse model

Traumatic brain injury (TBI) is the leading cause of death in young people and can cause cognitive and motor dysfunction and disruptions in functional connectivity between brain regions. In human TBI patients and rodent models of TBI, functional connectivity is decreased after injury. Recovery of connectivity after TBI is associated with improved cognition and memory, suggesting an important link between connectivity and functional outcome. We examined widespread alterations in functional connectivity following TBI using simultaneous widefield mesoscale GCaMP7c calcium imaging and electrocorticography (ECoG) in mice injured using the controlled cortical impact (CCI) model of TBI. Combining CCI with widefield cortical imaging provides us with unprecedented access to characterize network connectivity changes throughout the entire injured cortex over time. Our data demonstrate that CCI profoundly disrupts functional connectivity immediately after injury, followed by partial recovery over 3 weeks. Examining discrete periods of locomotion and stillness reveals that CCI alters functional connectivity and reduces theta power only during periods of behavioral stillness. Together, these findings demonstrate that TBI causes dynamic, behavioral state-dependent changes in functional connectivity and ECoG activity across the cortex.

neuroscience↗

bioRxiv2022

Cortical Parvalbumin-positive Interneuron Development and Function are Altered in the APC Conditional Knockout Mouse Model of Infantile Spasm Syndrome

Infantile Spasms syndrome (ISS) is a childhood epilepsy syndrome characterized by infantile or late onset spasms, abnormal neonatal EEG, and epilepsy. Few treatments exist for IS, clinical outcomes are poor, and the molecular and circuit-level etiologies of IS are not well understood. Multiple human ISS risk genes are linked to Wnt/{beta}-catenin signaling, a pathway which controls developmental transcriptional programs and promotes glutamatergic excitation via {beta}-catenins role as a synaptic scaffold. We previously showed that deleting adenomatous polyposis coli (APC), a component of the {beta}-catenin destruction complex, in excitatory neurons (APC cKO mice, APCfl/fl x CaMKIICre) in mice increased {beta}-catenin levels in developing glutamatergic neurons and led to infantile behavioral spasms, abnormal neonatal EEG, and adult epilepsy. Here, we tested the hypothesis that the development of inhibitory GABAergic interneurons (INs) is disrupted in APC cKOs. IN dysfunction is implicated in human ISS, is a feature of other rodent models of ISS and may contribute to the manifestation of spasms and seizures. We found that parvalbumin positive INs (PV+INs), an important source of cortical inhibition, were decreased in number, underwent disproportionate developmental apoptosis, and had altered dendrite morphology at P9, the peak time of behavioral spasms. PV+INs received excessive excitatory input and their intrinsic ability to fire action potentials was reduced at all timepoints examined (P9, P14, P60). Subsequently, synaptic inhibition of pyramidal neurons was uniquely altered in the somatosensory cortex of APC cKO mice at all ages, with both decreased inhibition at P14 and enhanced inhibition at P9 and P60. These results indicate that inhibitory circuit dysfunction occurs in APC cKOs and, along with known changes in excitation, may contribute to ISS-related phenotypes. Significance StatementInfantile spasms syndrome (ISS) is a devastating epilepsy with limited treatment options and poor clinical outcomes. The molecular, cellular, and circuit disruptions that cause infantile spasms and seizures are largely unknown, but inhibitory GABAergic interneuron dysfunction has been implicated in rodent models of ISS and may contribute to human ISS. Here, we utilize a rodent model of ISS, the APC cKO mouse, in which {beta}-catenin signaling is increased in excitatory neurons. This results in altered parvalbumin-positive GABAergic interneuron development and inhibitory synaptic dysfunction throughout life, showing that pathology arising in excitatory neurons can initiate long-term interneuron dysfunction. Our findings further implicate GABAergic dysfunction in ISS, even when pathology is initiated in other neuronal types.

neuroscience↗