Deficient DNA base-excision repair in the forebrain leads to a sex-specific anxiety-like phenotype in mice

Abstract

Background Neuropsychiatric disorders, such as schizophrenia (SZ) and autism spectrum disorder (ASD), are common, multi-factorial and multi-symptomatic disorders. Ample evidence implicates oxidative stress, deficient repair of oxidative DNA lesions and DNA damage in the development of these disorders. However, it remains unclear whether insufficient DNA repair and resulting DNA damage are causally connected to their aetiopathology, or if increased levels of DNA damage observed in patient tissues merely accumulate as a consequence of cellular dysfunction. To assess a potential causal role for deficient DNA repair in the development of these disorders, we behaviourally characterized a mouse model in which CaMKIIa-Cre-driven postnatal conditional knockout (KO) of the core base-excision repair (BER) protein XRCC1 leads to accumulation of unrepaired DNA damage in the forebrain. Results CaMKIIa-Cre expression caused specific deletion of XRCC1 in the dorsal dentate gyrus (DG), CA1 and CA2 and the amygdala and led to increased DNA damage therein. While motor coordination, cognition and social behaviour remained unchanged, XRCC1 KO in the forebrain caused increased anxiety-like behaviour in males, but not females, as assessed by the light–dark box and open field tests. Conversely, in females but not males, XRCC1 KO caused an increase in learned fear-related behaviour in a cued (Pavlovian) fear conditioning test and a contextual fear extinction test. The relative density of the GABA(A) receptor alpha 5 subunit (GABRA5) was reduced in the amygdala and the dorsal CA1 in XRCC1 KO females, whereas male XRCC1 KO animals exhibited a significant reduction of GABRA5 density in the CA3. Finally, assessment of fast-spiking, parvalbumin-positive (PV) GABAergic interneurons revealed a significant increase in the density of PV+ cells in the DG of male XRCC1 KO mice, while females remained unchanged. Conclusions Our results suggest that accumulation of unrepaired DNA damage in the forebrain alters the GABAergic neurotransmitter system and causes behavioural deficits in relation to innate and learned anxiety in a sex-dependent manner. Moreover, the data uncover a previously unappreciated connection between BER deficiency, unrepaired DNA damage in the hippocampus and a sex-specific anxiety-like phenotype with implications for the aetiology and therapy of neuropsychiatric disorders.

BRCA1 heterozygosity promotes DNA damage-induced senescence in a sex-specific manner following repeated mild traumatic brain injury

“…This may suggest that changes in anxiety occur in both sexes but are captured differently based on sex. In support of this, a recent study investigating the effects of deficient DNA repair on multi-symptomatic disorders found that mice with a conditional knockout for XRCC1 (i.e., a BER protein) displayed increased anxiety in males using the light–dark box test, while increased fear learning was observed in females using fear conditioning ( Mueller et al, 2022 ). Thus, altered DNA repair, elicited here by a BRCA1 heterozygous knockout, may work in a similar manner to differentially alter anxiety-related behaviours in both males and females with rmTBI.…”

Ultrarare Variants in DNA Damage Repair Genes in Pediatric Acute-Onset Neuropsychiatric Syndrome or Acute Behavioral Regression in Neurodevelopmental Disorders

“…The idea that DNA repair deficits underlie PANS and acute decompensation in NDD is novel, although studies linking DDR to behavior have been described. For example, postmitotic genome instability in neurons can lead to behavioral alterations and neurodegenerative disorders, and genetic studies show that DNA repair genes are involved in genetic subgroups of ASD and NDDs including most of the genes described in this report (e.g., PPM1D, ATM, ATR, 53BP1, FANCE, FANCI, and FANCP/SLX4) [113][114][115][116][117][118][119][120] .…”

The missing hallmark of health: psychosocial adaptation

“…DDR also engages the cGAS/STING pathway and stimulates a non-cell-autonomous response that facilitates homeostasis maintenance. However, deregulated DDR causes uncontrolled inflammation and tissue damage, including in the CNS [ 254 , 255 ]. Impaired DNA damage repair in concert with mitochondrial dysfunction is a common feature of diverse psychiatric disorders [ 255 , 256 ].…”