Abstract
Cognitive deficits and positive symptoms in schizophrenia have both been linked to hippocampal dysfunction. Recently, subregion-specific aberrant and maladaptive hippocampal synaptic plasticity has been suggested as one of the mechanistic underpinnings. The subiculum is the final output hub of the hippocampus and orchestrates hippocampal information transfer to other brain regions. While most CA1 pyramidal neurons show regular-spiking behavior, subicular output neurons comprise bursting and regular-firing pyramidal cells. These two cell types target different brain regions and express unique forms of synaptic plasticity. Here, we used a single systemic application of the noncompetitive glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonist MK-801 to model first-episode psychosis in rats and studied long-term potentiation (LTP) in subicular regular-firing cells in acute hippocampal slices. Previously, we have reported a facilitation of a presynaptic, late-onset LTP in subicular bursting pyramidal cells after systemic NMDAR antagonism. Here, we show that single systemic NMDAR antagonist application also facilitates the induction of a noncanonical, but postsynaptic NMDAR-independent LTP in ventral subicular but not in CA1 regular-firing pyramidal cells. This form of LTP was dependent on D1/D5 dopamine receptor activation. Activation of D1/D5 dopamine receptors by a specific agonist mimicked and occluded LTP induced by electrical high-frequency stimulation (HFS). Furthermore, our results indicate that this form of LTP relies on postsynaptic Ca2+ signaling and requires the activation of protein kinase A. Considering the pivotal role of the subiculum as information gatekeeper between the hippocampus and other brain regions, this aberrant LTP in ventral subicular regular-firing neurons is expected to interfere with physiological hippocampal output processing and might thereby contribute to hippocampal dysfunction in psychotic events.
Highlights
One percent of the global population is affected by schizophrenia
As systemic N-methyl-D-aspartate receptor (NMDAR) antagonism has been reported to facilitate a noncanonical late-onset long-term potentiation (LTP) at CA1-subiculum synapses to bursting pyramidal cells (Bartsch et al, 2015), we first studied whether this holds true for ventral CA1-subiculum synapses to regular-firing pyramidal cells
In MK-801-treated rats, the subthreshold high-frequency stimulation (HFS) induced stable LTP appearing as a lasting late-onset increase in EPSP amplitudes in subicular regular-firing pyramidal cells (2.12 ± 0.28, n = 7/5, p < 0.01; Figures 1C–E)
Summary
One percent of the global population is affected by schizophrenia. This multifaceted, heterogeneous psychiatric disorder is characterized by positive symptoms, i.e., delusions or hallucinations, negative symptoms, e.g., anhedonia, and cognitive symptoms including aberrant hippocampus-dependent memory encoding and retrieval as well as novelty detection (Heckers et al, 1998; Zierhut et al, 2010; Tamminga et al, 2012b; Pirnia et al, 2015; Ragland et al, 2015; Schott et al, 2015). Certain cognitive facets of schizophrenia can satisfactorily be modeled and studied in rodents by administering antagonists of the glutamatergic N-methyl-D-aspartate receptor (NMDAR, Neill et al, 2010). This rodent psychosis model originates from the NMDAR hypofunction concept which builds on the observation that acutely given NMDAR antagonists can induce psychosis in healthy humans similar to positive, negative and cognitive symptoms of schizophrenia (Luby et al, 1959). We used a single systemic application of the noncompetitive
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