Hippocampal Dysfunction in Schizophrenia and Aberrant Hippocampal Synaptic Plasticity in Rodent Model Psychosis: a Selective Review.

Schizophrenia is a complex, heterogeneous psychiatric disorder that affects about 1% of the global population. Hippocampal dysfunction has been linked to both cognitive deficits and positive symptoms in schizophrenia. Here, we briefly review current findings on disrupted hippocampal processing from a clinical perspective before concentrating on preclinical studies of aberrant hippocampal synaptic plasticity using the N-methyl-D-aspartate receptor hypofunction model of psychosis and related findings from genetic models. Taken together, the results put the case for maladaptive hippocampal synaptic plasticity and its extrinsic connections as mechanistic underpinnings of cognitive impairments in schizophrenia.

Stress-Induced Enhanced Long-Term Potentiation and Reduced Threshold for N-Methyl-D-Aspartate Receptor- and ß-Adrenergic Receptor-Mediated Synaptic Plasticity in Rodent Ventral Subiculum.

Stress is a biologically relevant signal and can modulate hippocampal synaptic plasticity. The subiculum is the major output station of the hippocampus and serves as a critical hub in the stress response network. However, stress-associated synaptic plasticity in the ventral subiculum has not been adequately addressed. Therefore, we investigated the impact of a single exposure to an inherently stressful two-way active avoidance conditioning on the induction of long-term potentiation (LTP) at CA1-subiculum synapses in ventral hippocampal slices from young adult rats 1 day after stressor exposure. We found that acute stress enhanced LTP and lowered the induction threshold for a late-onset LTP at excitatory CA1 to subicular burst-spiking neuron synapses. This late-onset LTP was dependent on the activation of ß-adrenergic and glutamatergic N-methyl-D-aspartate receptors and independent of D1/D5 dopamine receptor activation. Thereby, we present a cellular mechanism that might contribute to behavioral stress adaptation after acute stressor exposure.

Noncanonical, Dopamine-Dependent Long-Term Potentiation at Hippocampal Output Synapses in a Rodent Model of First-Episode Psychosis.

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.

Impaired anandamide/palmitoylethanolamide signaling in hippocampal glutamatergic neurons alters synaptic plasticity, learning, and emotional responses.

Endocannabinoid signaling via anandamide (AEA) is implicated in a variety of neuronal functions and considered a promising therapeutic target for numerous emotion-related disorders. The major AEA degrading enzyme is fatty acid amide hydrolase (FAAH). Genetic deletion and pharmacological inhibition of FAAH reduce anxiety and improve emotional responses and memory in rodents and humans. Complementarily, the mechanisms and impact of decreased AEA signaling remain to be delineated in detail. In the present study, using the Cre/loxP system combined with an adeno-associated virus (AAV)-mediated delivery system, FAAH was selectively overexpressed in hippocampal CA1-CA3 glutamatergic neurons of adult mice. This approach led to specific FAAH overexpression at the postsynaptic site of CA1-CA3 neurons, to increased FAAH enzymatic activity, and, in consequence, to decreased hippocampal levels of AEA and palmitoylethanolamide (PEA), but the levels of the second major endocannabinoid 2-arachidonoyl glycerol (2-AG) and of oleoylethanolamide (OEA) were unchanged. Electrophysiological recordings revealed an enhancement of both excitatory and inhibitory synaptic activity and of long-term potentiation (LTP). In contrast, excitatory and inhibitory long-term depression (LTD) and short-term synaptic plasticity, apparent as depolarization-induced suppression of excitation (DSE) and inhibition (DSI), remained unaltered. These changes in hippocampal synaptic activity were associated with an increase in anxiety-like behavior, and a deficit in object recognition memory and in extinction of aversive memory. This study indicates that AEA is not involved in hippocampal short-term plasticity, or eLTD and iLTD, but modulates glutamatergic transmission most likely via presynaptic sites, and that disturbances in this process impair learning and emotional responses.

Enhanced dopamine-dependent hippocampal plasticity after single MK-801 application.

Dopaminergic hyperfunction and N-methyl-D-aspartate receptor (NMDAR) hypofunction have both been implicated in psychosis. Dopamine-releasing drugs and NMDAR antagonists replicate symptoms associated with psychosis in healthy humans and exacerbate symptoms in patients with schizophrenia. Though hippocampal dysfunction contributes to psychosis, the impact of NMDAR hypofunction on hippocampal plasticity remains poorly understood. Here, we used an NMDAR antagonist rodent model of psychosis to investigate hippocampal long-term potentiation (LTP). We found that single systemic NMDAR antagonism results in a region-specific, presynaptic LTP at hippocampal CA1-subiculum synapses that is induced by activation of D1/D5 dopamine receptors and modulated by L-type voltage-gated Ca(2+) channels. Thereby, our findings may provide a cellular mechanism how NMDAR antagonism can lead to an enhanced hippocampal output causing activation of the hippocampus-ventral tegmental area-loop and overdrive of the dopamine system.