Abstract
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.
Highlights
GABAergic interneurons mediate several key features throughout the central nervous system
We investigated the effects of GABAergic ablation in two different brain structures and for varying incubation periods after saporin-conjugated anti-vesicular GABA transporter antibodies (SAVAs) administration: >14 days of incubation after SAVA application were used to study long-term effects of GABAergic depletion in the prelimbic cortex (PrL) and dorsal hippocampus (dHPC), and
SAVA treatment caused a trend towards a decreased latency for entering the light compartment of the Dark-Light box (D-L box), without altering the frequency to enter the light compartment or the time spent in it (Figures 1D2,3)
Summary
GABAergic interneurons mediate several key features throughout the central nervous system. They are important for the equilibrium between excitatory and inhibitory inputs, which in turn is necessary for a functioning neuronal network (Markram et al, 2004; Kullmann et al, 2012). GABAergic interneurons represent only about one fifth of cortical neurons and even less in the dorsal hippocampus (dHPC; Jinno and Kosaka, 2010; Lehmann et al, 2012), a disturbance of GABAergic development or the GABAergic network quickly leads to detrimental consequences as seen in neurological and neuropsychiatric disorders, such as epilepsy, depression or schizophrenia (Sanacora et al., 2000; Wong et al, 2003; Hossein Fatemi et al, 2005; Inan et al, 2013; Gilani et al, 2014). The positive symptoms are difficult to mimic in animal models; a distinction is used for endophenotypes with little face
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