Trace fear conditioning depends on NMDA receptor activation and protein synthesis within the dorsal hippocampus of mice.

Various lesion studies demonstrated that trace but not delay fear conditioning requires an intact hippocampal formation. Our present study examined the role of NMDA receptor activation and protein synthesis within the dorsal hippocampus for acquisition of fear memories following trace (5-s trace) and delay conditioning. To this end male C57BL/6JOlaHsd mice were chronically implanted with guide cannulae targeting the dorsal hippocampus. Fifteen minutes before conditioning mice received a bilateral intrahippocampal injection of either the NMDA receptor antagonist AP5 (0.5 or 1 microg per 0.5 microl per side) or of anisomycin, an inhibitor of protein synthesis (62.5 microg per 0.5 microl per side). Control mice were treated with vehicle (Ringer's solution). Blocking NMDA receptors before trace but not delay conditioning dose-dependently attenuated the freezing response to the tone as assessed 24 h after conditioning. The same findings were obtained after blocking protein synthesis within the dorsal hippocampus. These data indicate that the hippocampus shows synaptic plasticity during trace conditioning that requires an activation of NMDA receptors and protein synthesis as prerequisites for the acquisition of fear memory.

Distinct behavioral consequences of short-term and prolonged GABAergic depletion in prefrontal cortex and dorsal hippocampus.

GABAergic interneurons are essential for a functional equilibrium between excitatory and inhibitory impulses throughout the CNS. Disruption of this equilibrium can lead to various neurological or neuropsychiatric disorders such as epilepsy or schizophrenia. Schizophrenia itself is clinically defined by negative (e.g., depression) and positive (e.g., hallucinations) symptoms as well as cognitive dysfunction. GABAergic interneurons are proposed to play a central role in the etiology and progression of schizophrenia; however, the specific mechanisms and the time-line of symptom development as well as the distinct involvement of cortical and hippocampal GABAergic interneurons in the etiology of schizophrenia-related symptoms are still not conclusively resolved. Previous work demonstrated that GABAergic interneurons can be selectively depleted in adult mice by means of saporin-conjugated anti-vesicular GABA transporter antibodies (SAVAs) in vitro and in vivo. Given their involvement in schizophrenia-related disease etiology, we ablated GABAergic interneurons in the medial prefrontal cortex (mPFC) and dorsal hippocampus (dHPC) in adult male C57BL/6N mice. Subsequently we assessed alterations in anxiety, sensory processing, hyperactivity and cognition after long-term (>14 days) and short-term (<14 days) GABAergic depletion. Long-term GABAergic depletion in the mPFC resulted in a decrease in sensorimotor-gating and impairments in cognitive flexibility. Notably, the same treatment at the level of the dHPC completely abolished spatial learning capabilities. Short-term GABAergic depletion in the dHPC revealed a transient hyperactive phenotype as well as marked impairments regarding the acquisition of a spatial memory. In contrast, recall of a spatial memory was not affected by the same intervention. These findings emphasize the importance of functional local GABAergic networks for the encoding but not the recall of hippocampus-dependent spatial memories.

Maternal inexperience as a risk factor of innate fear and PTSD-like symptoms in mice.

In laboratory rats and mice, differences in maternal care during the first week of life have been shown to exert long-lasting consequences on cognitive functioning and stress processing of the offspring. Such epigenetic programming is also assumed to play an important role in the transgenerational transmission of PTSD in humans. Here we studied whether even subtle within-subject differences in maternal care - caused by increasing mothering experience from the first to the second litter - can determine subsequent vulnerability for PTSD-like behaviour. To assess the influence of maternal experience on different components of fear, we analysed the adult male offspring of two subsequent litters (offspring 1, 2) from the same parental C57BL/6NCrl (B6N) and C57BL/6JOla (B6JOla) mice for (i) their innate anxiety behaviour on a modified hole board and (ii) their vulnerability to develop long-lasting PTSD-like fear symptoms ("hyperarousal", contextually conditioned fear) following perception of an inescapable foot shock. Increasing maternal experience reduced the animals' innate fear on the modified hole board (more exploration, less inhibition), the acute stress reaction to the shock and - one month after trauma - the levels of hyperarousal-like behaviour in the PTSD-prone B6N strain. In contrast, both acquisition and extinction of contextually conditioned fear were increased in the second offspring, representing cognitive flexibility. A factor analysis showed that innate fear, "hyperarousal" and conditioned fear represent independent behavioural dimensions. In conclusion, the present study identifies maternal inexperience as a risk factor for the development of PTSD-like symptoms. This effect - occurring in inbred mice on an almost identical genetic background - emphasizes the impact of epigenetic factors in PTSD-like behaviour.