Down syndrome (DS) is the most common form of intellectual disability. The cognitive alterations in DS are thought to depend on brain regions critical for learning and memory such as the prefrontal cortex (PFC) and the hippocampus (HPC). Neuroimaging studies suggest that increased brain connectivity correlates with lower intelligence quotients (IQ) in individuals with DS; however, its contribution to cognitive impairment is unresolved. We recorded neural activity in the PFC and HPC of the trisomic Ts65Dn mouse model of DS during quiet wakefulness, natural sleep, and the performance of a memory test. During rest, trisomic mice showed increased theta oscillations and cross-frequency coupling in the PFC and HPC while prefrontal–hippocampal synchronization was strengthened, suggesting hypersynchronous local and cross-regional processing. During sleep, slow waves were reduced, and gamma oscillations amplified in Ts65Dn mice, likely reflecting prolonged light sleep. Moreover, hippocampal sharp-wave ripples were disrupted, which may have further contributed to deficient memory consolidation. Memory performance in euploid mice correlated strongly with functional connectivity measures that indicated a hippocampal control over memory acquisition and retrieval at theta and gamma frequencies, respectively. By contrast, trisomic mice exhibited poor memory abilities and disordered prefrontal–hippocampal functional connectivity. Memory performance and key neurophysiological alterations were rescued after 1 month of chronic administration of a green tea extract containing epigallocatequin-3-gallate (EGCG), which improves executive function in young adults with DS and Ts65Dn mice. Our findings suggest that abnormal prefrontal–hippocampal circuit dynamics are candidate neural mechanisms for memory impairment in DS.

Atypical antipsychotic drugs (APDs) used to treat positive and negative symptoms in schizophrenia block serotonin receptors 5-HT 2A R and dopamine receptors D 2 R and stimulate 5-HT 1A R directly or indirectly. However, the exact cellular mechanisms mediating their therapeutic actions remain unresolved. We recorded neural activity in the prefrontal cortex (PFC) and hippocampus (HPC) of freely-moving mice before and after acute administration of 5-HT 1A R, 5-HT 2A R and D 2 R selective agonists and antagonists and atypical APD risperidone. We then investigated the contribution of the three receptors to the actions of risperidone on brain activity via statistical modeling and pharmacological reversal (risperidone + 5-HT 1A R antagonist WAY-100635, risperidone + 5-HT 2A/2C R agonist DOI, risperidone + D 2 R agonist quinpirole). Risperidone, 5-HT 1A R agonism with 8-OH-DPAT, 5-HT 2A R antagonism with M100907, and D 2 R antagonism with haloperidol reduced locomotor activity of mice that correlated with a suppression of neural spiking, power of theta and gamma oscillations in PFC and HPC, and reduction of PFC-HPC theta phase synchronization. By contrast, activation of 5-HT 2A R with DOI enhanced high-gamma oscillations in PFC and PFC-HPC high gamma functional connectivity, likely related to its hallucinogenic effects. Together, power changes, regression modeling and pharmacological reversals suggest an important role of 5-HT 1A R agonism and 5-HT 2A R antagonism in risperidone-induced alterations of delta, beta and gamma oscillations, while D 2 R antagonism may contribute to risperidone-mediated changes in delta oscillations. This study provides novel insight into the neural mechanisms for widely prescribed psychiatric medication targeting the serotonin and dopamine systems in two regions involved in the pathophysiology of schizophrenia.

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