Intervention During Adolescence Leads to Long-Lasting Rescue of Network Dysfunction in a Model of Schizophrenia

Post by Amanda McFarlan

What's the science?

Prefrontal cortex (PFC) maturation in late adolescence is known to be disrupted in individuals with schizophrenia. A key feature of this maturation process involves the synchronization of the PFC to other cortical and limbic brain regions through high-frequency oscillatory neuronal activity. This synchronization process is mediated by inhibitory neuron signaling from parvalbumin (PV)-expressing interneurons. The ventral hippocampus also plays a role in the maturation process of the PFC, by promoting inhibitory neuron signaling. Mouse models with chromosome 16 deletions, including the LgDel mouse model, have been useful in studying the pathological changes associated with the onset of schizophrenia. This week in Cell, Mukherjee and colleagues investigated whether cognitive and network dysfunction could be rescued in the LgDel mouse model of schizophrenia if treatments were administered during adolescence.

How did they do it?

To validate the LgDel mouse model as a model of schizophrenia, the authors investigated whether LgDel mice displayed similar phenotypes to those observed in humans with schizophrenia, namely, deficits in network synchronization and cognition. They used two behavioural approaches to test for impairments in cognition commonly associated with schizophrenia: goal-directed learning (associated with deficits in the PFC) and social recognition (associated with deficits in the hippocampus). To determine whether network synchronization was disrupted in LgDel mice, they recorded local field potentials in the medial PFC in awake, behaving animals and assessed the oscillatory activity of neurons in this region. Next, the authors used the PSAM/PSEM chemogenetic approach (allows for select activation of PV interneurons) to investigate whether PV interneuron signaling was disrupted in LgDel mice. Recording electrodes were implanted in the PFC of both LgDel mice and control mice to measure neural activity while selectively activating PV interneurons. Then, the authors tested whether the systemic administration of a dopamine receptor-2 antagonist (commonly used to treat the symptoms of schizophrenia) would rescue deficits in network function, cognition and PV interneuron signaling in LgDel mice. Next, they targeted the administration of dopamine receptor-2 antagonists to either two regions of the hippocampus (dorsal and ventral) or two regions of the PFC (medial PFC and the lateral orbital cortex) during several different time windows to determine the specific conditions that would allow for long-lasting effects from antipsychotic treatment. Finally, the authors investigated the role of PV interneurons in rescuing the LgDel mouse phenotype in late-adolescence by applying repeated chemogenetic activation of PV interneurons in either the medial PFC or ventral hippocampus between postnatal day 60 and 70 (late-adolescence).

What did they find?

The authors determined that LgDel mice exhibit similar deficits in cognition as individuals with schizophrenia. They also found that, compared to controls, adult LgDel mice had a power deficit in the oscillatory activity of medial PFC neurons in the high gamma range, which may be indicative of a reduction in the activity of fast-spiking PV interneurons. In support of this, they revealed that interneurons had lower firing rates in LgDel mice compared to controls. Next, the authors showed that chemogenetic activation of PV interneurons in the medial PFC led to a robust increase in inhibitory neuron firing rates in control mice, but not LgDel mice, suggesting that PV interneuron signaling is disrupted in LgDel mice. Then, the authors determined that a single systemic dose of a dopamine receptor-2 antagonist in LgDel mice was able to transiently rescue the observed deficit in oscillatory activity in the gamma range and significantly improve performance during a social recognition task. Next, they found that targeted administration of a dopamine receptor-2 antagonist the ventral hippocampus or the medial PFC, but not the dorsal hippocampus or the lateral orbital cortex, led to long-lasting improvements in PV expression levels, PV interneuron activity and cognition. They showed that these long-lasting improvements only occurred if the dopamine receptor-2 antagonist was delivered in late-adolescence, suggesting that this period may be critical for treatment intervention. Finally, the authors revealed that repeated chemogenetic activation of PV interneurons targeted to the ventral hippocampus or medial PFC in late-adolescence resulted in similar long-lasting improvements in network activity and cognition as observed with dopamine receptor-2 antagonist administration. Together, these findings suggest that increasing the activity of PV interneurons within the medial PFC-ventral hippocampus axis during late adolescence may be critical to prevent progression to schizophrenia-like network and cognitive deficits in LgDel mice.

What's the impact?

This is the first study to show that network deficits and cognitive impairments in LgDel mice can be prevented by targeted activation of PV interneurons in the ventral hippocampus and medial PFC during late adolescence. The authors showed that these improvements are long-lasting and can be achieved by chemogenetic activation of PV interneurons as well as administration of dopamine receptor-2 antagonists. Together, these findings provide insight into the mechanisms that may underly the pathological changes during late adolescence that lead to the onset of schizophrenia as well as potential treatments that may be useful to prevent progression to pathological changes in predisposed individuals.

Mukherjee et al. Long-Lasting Rescue of Network and Cognitive Dysfunction in a Genetic Schizophrenia Model (2019). Access the original scientific publication here.