Endogenous neuronal DNA double-strand breaks are not sufficient to drive brain aging and neurodegeneration.

Loss of genomic information due to the accumulation of somatic DNA damage has been implicated in aging and neurodegeneration . Somatic mutations in human neurons increase with age , but it is unclear whether this is a cause or a consequence of brain aging. Here, we clarify the role of endogenous, neuronal DNA double-strand breaks (DSBs) in brain aging and neurodegeneration by generating mice with post-developmental inactivation of the classical non-homologous end-joining (C-NHEJ) core factor Xrcc4 in forebrain neurons.

Spatial Coding Dysfunction and Network Instability in the Aging Medial Entorhinal Cortex.

Across species, spatial memory declines with age, possibly reflecting altered hippocampal and medial entorhinal cortex (MEC) function. However, the integrity of cellular and network-level spatial coding in aged MEC is unknown. Here, we leveraged electrophysiology to assess MEC function in young, middle-aged, and aged mice navigating virtual environments.

Neuronal activation of G EGL-30/GNAQ late in life rejuvenates cognition across species.

Loss of cognitive function with age is devastating. EGL-30/GNAQ and G signaling pathways are highly conserved between C. elegans and mammals, and murine Gnaq is enriched in hippocampal neurons and declines with age.

Loss of neuronal Tet2 enhances hippocampal-dependent cognitive function.

DNA methylation has emerged as a critical modulator of neuronal plasticity and cognitive function. Notwithstanding, the role of enzymes that demethylate DNA remain to be fully explored. Here, we report that loss of ten-eleven translocation methylcytosine dioxygenase 2 (Tet2), which catalyzes oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), in adult neurons enhances cognitive function.

Microglial GPR56 is the molecular target of maternal immune activation-induced parvalbumin-positive interneuron deficits.

Parvalbumin-positive (PV) interneurons play a critical role in maintaining circuit rhythm in the brain, and their reduction is implicated in autism spectrum disorders. Animal studies demonstrate that maternal immune activation (MIA) leads to reduced PV interneurons in the somatosensory cortex and autism-like behaviors. However, the underlying molecular mechanisms remain largely unknown.

Context-Specific Transcription Factor Functions Regulate Epigenomic and Transcriptional Dynamics during Cardiac Reprogramming.

Ectopic expression of combinations of transcription factors (TFs) can drive direct lineage conversion, thereby reprogramming a somatic cell's identity. To determine the molecular mechanisms by which Gata4, Mef2c, and Tbx5 (GMT) induce conversion from a cardiac fibroblast toward an induced cardiomyocyte, we performed comprehensive transcriptomic, DNA-occupancy, and epigenomic interrogation throughout the reprogramming process. Integration of these datasets identified new TFs involved in cardiac reprogramming and revealed context-specific roles for GMT, including the ability of Mef2c and Tbx5 to independently promote chromatin remodeling at previously inaccessible sites.