Subchronic phencyclidine treatment in adult mice increases GABAergic transmission and LTP threshold in the hippocampus

Abstract

Repeated administration of non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) to rodents causes long-lasting deficits in cognition and memory, and has effects on behaviors that have been suggested to be models of the cognitive impairment associated with schizophrenia (CIAS). Despite this being a widely studied animal model, little is known about the long lasting changes in synapses and circuits that underlie the altered behaviors. Here we examined synaptic transmission ex-vivo in the hippocampus of mice after a subchronic PCP (scPCP) administration regime. We found that after at least one week of drug free washout period when mice have impaired cognitive function, the threshold for long term potentiation (LTP) of CA1 excitatory synapses was elevated. This elevated LTP threshold was directly related to increased inhibitory input to CA1 pyramidal cells through increased activity of GABAergic neurons. These results suggest repeated PCP administration causes a long-lasting metaplastic change in the inhibitory circuits in the hippocampus that results in impaired LTP, and could contribute to the deficits in hippocampal-dependent memory in PCP-treated mice. Changes in GABA signaling have been described in patients with schizophrenia, therefore our results support using scPCP as a model of CIAS.

GLYX-13 (rapastinel) ameliorates subchronic phencyclidine- and ketamine-induced declarative memory deficits in mice

“…The ketamine- and PCP-induced deficits in rodent NOR is likely due to the disruption of synaptic function and plasticity [27,28]. Therefore, the ability of rapastinel to prevent and reverse the effects of ketamine and PCP to cause deficits in NOR may result from facilitation of NMDAR- and GABAergic- dependent synaptic plasticity in hippocampus [28], perirhinal and entorhinal cortices, and medial prefrontal cortex and preservation of, or restoration, of functional integration of these critical brain areas for learning and memory [29].…”

“…Therefore, the ability of rapastinel to prevent and reverse the effects of ketamine and PCP to cause deficits in NOR may result from facilitation of NMDAR- and GABAergic- dependent synaptic plasticity in hippocampus [28], perirhinal and entorhinal cortices, and medial prefrontal cortex and preservation of, or restoration, of functional integration of these critical brain areas for learning and memory [29]. In rat hippocampal slices, rapastinel preferentially enhanced conductance of GluN2B-containing NMDARs at the Schaffer collateral-CA1 synapses in vitro [30], and also enhanced the magnitude of long-term potentiation (LTP) of synaptic transmission while simultaneously reducing that of long-term depression (LTD)[30,31].…”

Potentiating α2 subunit containing perisomatic GABAA receptors protects against seizures in a mouse model of Dravet syndrome

“…Horizontal hippocampal slices (350 µm) were prepared from postnatal days 14-16 (P14-P16) mice as described previously (Fernandes et al 2015;Nomura et al 2016). Briefly, brain sections were prepared in ice-cold sucrose-slicing artificial cerebrospinal fluid (ACSF) containing the following (in mM): 85 NaCl, 2.5 KCl, 1.25 NaH 2 PO 4 , 25 NaHCO 3 , 25 glucose, 75 sucrose, 0.5 CaCl 2 , and 4 MgCl 2 with 10 µM DL-APV and 100 µM kynurenate.…”

Potentiating α2 subunit containing perisomatic GABAA receptors protects against seizures in a mouse model of Dravet Syndrome

“…Horizontal hippocampal slices (350 μm) were prepared from postnatal day 14 -16 (P14 -P16) mice as described previously (Fernandes et al, 2015;Nomura et al, 2016). Briefly, brain sections were prepared in ice-cold sucrose-slicing artificial CSF (ACSF) containing the following (in mM): 85 NaCl, 2.5 KCl, 1.25 NaH 2 PO 4 , 25 NaHCO 3 , 25 glucose, 75 sucrose, 0.5 CaCl 2 , and 4 MgCl 2 with 10 μM DL-APV and 100 μM kynurenate.…”