Table 1 Factors with genetic PTSD/PTSD feature association in human and corresponding findings in animal models
Gene (human findings) | Finding in animal model(s) |
|---|---|
HPA stress axis | |
GR stimulation improves fear extinction after stress-enhanced fear conditioning [53] GR expression is increased in the PFC after single prolonged stress [213] Transcriptional changes of the GR pathway in amygdala and hippocampus after predator scent [52] GR mediates potentiation of fear memory after single prolonged stress [214] | |
FKBP5 knockout prevents age-induced impairment of stress resilience [217] FKBP5 knockdown in the rat infralimbic cortex enhances extinction [218] | |
… Shows interaction with juvenile adversity on PTSD development [33, 36] | Reduced FKBP5 in expression in the rat PFC after early-life stress [219] Lastingly increased FKBP5 expression in rat BLA after chronic mild stress in adolescences [220] |
Conditional ablation of CRHR1 from forebrain neurons impairs consolidation of remote fear memory [224] CRHR2 mediates stress-enhanced fear conditioning via Mek1/2 activation [97] CRHR2 knockdown in BNST provides resilience in a stress-enhanced fear learning paradigm [225] CRHR2 overexpression in BNST attenuates predator stress-induced fear in susceptible animals [226] | |
… Mediates the effect of juvenile adversity on cortisol response [227] | Transient prepubertal overexpesion of CRH in the forebrain increases vulnerability [228] Early-life stress × 5-HTT interaction controls CRH Promoter methylation in adult [229] |
PACAP / PAC1R [230] | PAC1R−/− show reduced anxiety [231] PACAP HET produce increased vulnerability to combined juvenile and adult chronic mild stress [232] |
Serotonergic system | |
5-HTT−/− mice show fear extinction deficits [237] 5-HTT inhibitor venlafaxine relieves forced swim stress after single prolonged stress [238] | |
… Mediates interaction of childhood adversity and sex on hippocampal volume [239] | 5-HTT mutation interacts with maternal separation stress to control HPA maturation and behavior in adult rats [240, 241] |
5-HT1A receptor [242] | 5-HT1A knockout shows increased context fear memory [243] 5-HT1A mediates fear extinction deficits after early-life stress [100] Increased 5-HT1A expression in dorsal raphe after single prolonged stress [244] 5-HT1A mediates recovery of inhibitory control in the dentate gyrus after juvenile stress [245] |
Dopaminergic system | |
Dopamine receptor 2 [246] | Regulation of DRD2 expression in N. accumbens by prenatal stress [247] Reduced DRD2 expression in amygdala after social stress induction of increased fear [248] |
Catechyl-O-methyltransferase [249] | — |
… Mediates lastingly increased cortisol levels in adolescents after stress [250] | COMT−/− mice are vulnerable to cannabinoid treatment in adolescence, altering PPI in adult [251] |
Glutamatergic system | |
mGluR5 [252] | Mediates stress-enhanced fear memory through interaction with Homer [98] |
GABAergic system | |
GAD2 knockout shows increased, generalized fear [254] GAD2 knockout displays extinction deficits [255] | |
GAD2 haplodeficient mice show resilience to fear generalization after juvenile stress [256] | |
GABAA receptor | Rescue of PTSD symptoms in single prolonged stress model by midazolam [257] |
… Interacts with childhood trauma towards risk for PTSD [258] | Altered GABAA receptor alpha subunit expression in juvenile stressed rats [259] Reduced allopregnanolone after social isolation and rescue of social isolation induced fear behavior by ganaxolone [260, 261] |
GABA-B receptor ... Only pharmacological evidence | Knockout of GABAB1a results in fear memory generalization [262] GABA-B antagonist induces fear generalization in mice [263] GABA-B antagonist blocks fear extinction in rats [264] |
Cannabinoid receptor 1 | Knockout mice show an increased response to repeated stress exposures [265] CB1 antagonist blocks conditioned fear extinction [266] Increased expression in dorsal striatum after a single prolonged stress [267] |
… Interacts with childhood abuse to increase fear in PTSD [268] | Disruption in adolescence alters adult anxiety-related behavior [269] |
Neuropeptides | |
Neuropeptide Y [270] | NPY mediates resilience to effects of predator odor exposure [155] Reduced expression is observed following chronic variable stress shock [271] Inhibition in the dentate gyrus impairs context salience determination in fear conditioning [110] |
Nociceptin/Orphanin FQ [272] | N/OFQ acts as anxiolytic following single prolonged stress in rats [273] |
Tachikinin 2 | Overexpression in central amygdala mediates consolidation of stress-enhanced fear in mice [274] |
Impaired fear extinction found in BDNF-e4 mutant mice [279] BDNF promoter methylation is increased in the hippocampus after psychosocial stress [280] Increased BDNF signaling is observed after single prolonged stress [49] BDNF cko show enhanced fear learning [281] BDNF knockdown in the hippocampus impairs fear extinction [282] Impaired fear extinction in BDNF Met-Val mutant mice [283] | |
… Child abuse moderatesVal66Met induced increase of threat reactivity in PTSD veterans [284] | Critical for context fear memory in adolescent mice [285] |
Oxytocin/OT Receptor [286] | Reduced anxiety of OT−/− males mice [287] Increased anxiety in OT−/− females [288] |
… Mediates effect of early-life stress on adult depression anxiety stress scale [289] | OT−/− mice show reduced vocalization during maternal separation [287] |
Others | |
APOE2−/− mice display lack of fear extinction [291, 292] APOE2−/− mice show increased response to chronic variable stress [292] | |
Interleukin-1 receptor [92] | IL-1−/− mice display increase in conditioned fear [89] Blockage of IL-1 in the hippocampus ameliorates stress-enhanced fear memory [95] |
S100B, only serum levels | Knockout mice show increased conditioned fear [93] Increased CSF levels found after maternal stress+adult shock [94] |
Regulator of G protein signaling 2 [91] | RGS2−/− mice show increased context fear memory [90] |
Voltage gated calcium channel subunit alpha 1C [293] | Enhanced fear memory in CACNA1C+/− mutant mice [294] |
ROR alpha [295] | ROR-A−/− mice show increased corticosterone response to novelty stress [296] |
… Mediates effect of early-life stress on posttraumatic stress response [297] | ROR-A promoter methylation upon maternal separation stress prevents differentiation of adult neural precursors [298] |
