Δ-9-Tetrahydrocannabinol treatment during adolescence and alterations in the inhibitory networks of the adult prefrontal cortex in mice subjected to perinatal NMDA receptor antagonist injection and to postweaning social isolation

Abstract

The prefrontal cortex (PFC) continues its development during adolescence and alterations in its structure and function, particularly of inhibitory networks, have been detected in schizophrenic patients. Since cannabis use during adolescence is a risk factor for this disease, our main objective was to investigate whether THC administration during this period might exacerbate alterations in prefrontocortical inhibitory networks in mice subjected to a perinatal injection of MK801 and postweaning social isolation. This double-hit model (DHM) combines a neurodevelopmental manipulation and the exposure to an aversive experience during early life; previous work has shown that DHM mice have important alterations in the structure and connectivity of PFC interneurons. In the present study we found that DHM had reductions in prepulse inhibition of the startle reflex (PPI), GAD67 expression and cingulate 1 cortex volume. Interestingly, THC by itself induced increases in PPI and decreases in the dendritic complexity of somatostatin expressing interneurons. Both THC and DHM reduced the density of parvalbumin expressing cells surrounded by perineuronal nets and, when combined, they disrupted the ratio between the density of puncta expressing excitatory and inhibitory markers. Our results support previous work showing alterations in parameters involving interneurons in similar animal models and schizophrenic patients. THC treatment does not modify further these parameters, but changes some others related also to interneurons and their plasticity, in some cases in the opposite direction to those induced by the DHM, suggesting a protective effect.

Parvalbumin Interneurons and Perineuronal Nets in the Hippocampus and Retrosplenial Cortex of Adult Male Mice After Early Social Isolation Stress and Perinatal NMDA Receptor Antagonist Treatment

“…Interestingly, we also observed alterations in the number of PV expressing neurons and PNNs in certain regions of the amygdala and the PFC of DHM mice (Castillo-Gómez et al, 2017 ; Garcia-Mompo et al, 2020 ) and PV+ neurons in the PFC of DHM rats (Gilabert-Juan et al, 2013 ). However, we still do not have information on the impact of this animal model on the PV expressing cells and PNNs of the hippocampus and the RSC of adult mice.…”

“…We believe that the DHM is still valid because in it the effects of the 2 factors are present (although independently). We have previously shown that other behavioral and neurochemical (in the PFC and the amygdala) changes relevant for schizophrenia are present in the DHM, sometimes contributed by one of the factors alone and sometimes through the interaction of both factors (Castillo-Gómez et al, 2017 ; Garcia-Mompo et al, 2020 ).…”

“…The perinatal injection of NMDAR antagonists combined with the postweaning social isolation rearing has been used as an animal model for schizophrenia, in which some behavioral, structural and neurochemical traits similar to those found in schizophrenic patients can be found. We have previously shown in mice that the combination of these paradigms in a double hit model (DHM) causes changes in anxiety and locomotor behaviors (Castillo-Gómez et al, 2017 ) and a decrease in prepulse inhibition of the startle reflex (Garcia-Mompo et al, 2020 ). In addition, we found that the volume, the structure and connectivity of excitatory and inhibitory neurons, and the expression of molecules related to inhibitory transmission and its plasticity were altered in the PFC and the amygdala (Castillo-Gómez et al, 2017 ; Garcia-Mompo et al, 2020 ).…”

“…We have previously shown in mice that the combination of these paradigms in a double hit model (DHM) causes changes in anxiety and locomotor behaviors (Castillo-Gómez et al, 2017 ) and a decrease in prepulse inhibition of the startle reflex (Garcia-Mompo et al, 2020 ). In addition, we found that the volume, the structure and connectivity of excitatory and inhibitory neurons, and the expression of molecules related to inhibitory transmission and its plasticity were altered in the PFC and the amygdala (Castillo-Gómez et al, 2017 ; Garcia-Mompo et al, 2020 ).…”

Cognitive Consequences of Social Isolation During COVID-19: side effects and treatments

“…Moreover, a low dose of corticosterone increased the expression of the activityregulated cytoskeletal associated protein (Arc) and improved long-term memory in socially isolated rats. Other studies have shown that inhibiting receptors via antagonist drugs might reverse SI impairment in rodents (79)(80)(81).…”