Serotonin 5-HT1A receptors modulate neural rhythms in prefrontal cortex and hippocampus and prefronto-hippocampal connectivity in alert mice

Theserotonergic system plays a crucial role in cognition and is a target of many psychiatric treatments. In particular, serotonin 5-HT1A receptors (5-HT1AR) in the prefrontal cortex and hippocampus play key roles in learning, memory, behavioral flexibility, and response inhibition. Here, we investigated how 5-HT1A receptors influence neural network dynamics in the prefrontal cortex and hippocampus and prefronto-hippocampal functional connectivity in alert mice. We found that pharmacological stimulation of 5-HT1AR with 8-OH-DPAT markedly reduces theta, beta, and high gamma oscillations in both areas and weakens prefronto-hippocampal phase synchronization at theta and beta frequencies. Pharmacological inhibition of 5-HT1A receptors with WAY-100635 reduces theta and high gamma oscillatory activity but increases beta and delta oscillations. It also weakens prefronto-hippocampal phase synchronization at theta frequencies. These results reveal that prefronto-hippocampal neurodynamics are highly sensitive to 5-HT1A manipulation and may be relevant for understanding the actions of psychiatric medication targeting the serotonergic system.Peer ReviewedPreprin

Reversible photocontrol of dopaminergic transmission in wild-type animals

Understanding the dopaminergic system is a priority in neurobiology and neuropharmacology. Dopamine receptors are involved in the modulation of fundamental physiological functions and dysregulation of dopaminergic transmission is associated with major neurological disorders. However, the available tools to dissect the endogenous dopaminergic circuits have limited specificity, reversibility, resolution, or require genetic manipulation. Here we introduce azodopa, a novel photoswitchable ligand that enables reversible spatiotemporal control of dopaminergic transmission. We demonstrate that azodopa activates D1-like receptors in vitro in a light-dependent manner. Moreover, it enables reversibly photocontrolling zebrafish motility on a time scale of seconds and allows separating the retinal component of dopaminergic neurotransmission. Azodopa increases the overall neural activity in the cortex of anesthetized mice and displays illuminationdependent activity in individual cells. Azodopa is the first photoswitchable dopamine agonist with demonstrated efficacy in wildtype animals and opens the way to remotely controlling dopaminergic neurotransmission for fundamental and therapeutic purposes

Neural substrates of psychotic-like states and cognitive impairment in a mouse model of schizophrenia and subsequent rescue by antipsychotic drugs

Disruption of communication in brain circuits involving the prefrontal cortex (PFC) and the hippocampus (HPC) has been suggested to be a hallmark characteristic of schizophrenia. Therefore, a better understanding of the prefrontal-hippocampal neural basis of schizophrenia’s symptoms is essential for the development of new treatments. In the present thesis, we investigated the alterations of prefrontal-hippocampal circuits in the phencyclidine, acute and subchronic (sPCP), mouse model of schizophrenia and how some of these alterations can be recovered by antipsychotic drugs. We recorded neural activity in the PFC and HPC of C57BL/6J mice. Acute administration of PCP produces hypersynchronization and disrupted communication of PFC-HPC pathways that are recovered by atypical antipsychotic drugs. Furthermore, the sPCP-treated mice showed brain state alterations in gamma oscillations and theta-gamma cross-frequency coupling. Notably, auditory perception, working memory and long-term memory were profoundly impaired in sPCP-treated mice and were accompanied by disrupted prefrontal-hippocampal functional connectivity. Finally, the subchronic risperidone treatment was able to recover memory deficits, but was unable to restore the basal circuit dynamics.Una de las características distintivas la esquizofrenia, es la perturbación de la comunicación de los circuitos cerebrales que incluyen la corteza prefrontal (CPF) y el hipocampo (HPC). Por lo tanto, un mejor entendimiento de las bases neurales de los circuitos prefronto-hipocampales durante los síntomas de la esquizofrenia es esencial para el desarrollo de nuevos tratamientos. En esta tesis, hemos investigado las alteraciones en los circuitos prefrontal-hipocampales en un modelo de esquizofrenia en ratones basado en el tratamiento de fenciclidina, agudo o subcrónico (sPCP), y cómo estas alteraciones pueden ser recuperadas por antipsicóticos Para poder llevar esto a cabo, hemos registrado actividad neural simultáneamente en la CPF y HPC de ratones C57BL/6J. La administración aguda de PCP produce híper sincronización y perturba la comunicación de los circuitos prefronto-hippocampales. Estas alteraciones pueden ser recuperadas por antipsicóticos atípicos. Además, los ratones tratados con sPCP muestran alteraciones de circuito en las oscilaciones gamma y en el acoplamiento cross-frecuencia theta-gamma. Particularmente, el tratamiento sPCP perjudica la percepción auditiva, la memoria de trabajo y la memoria a largo plazo. Todas estas alteraciones van acompañadas de alteraciones en la conectividad funcional de los circuitos prefronto-hipocampales. Finalmente, el tratamiento subcrónico de risperidona es capaz de recuperar los déficits de memoria, pero es incapaz de restaurar las dinámicas prefronto-hipocampales basales

Neural substrates of cognitive impairment in a NMDAR hypofunction mouse model of schizophrenia and partial rescue by risperidone

N-methyl D-aspartate receptor (NMDAR) hypofunction is a pathophysiological mechanism relevant for schizophrenia. Acute administration of the NMDAR antagonist phencyclidine (PCP) induces psychosis in patients and animals while subchronic PCP (sPCP) produces cognitive dysfunction for weeks. We investigated the neural correlates of memory and auditory impairments in mice treated with sPCP and the rescuing abilities of the atypical antipsychotic drug risperidone administered daily for two weeks. We recorded neural activities in the medial prefrontal cortex (mPFC) and the dorsal hippocampus (dHPC) during memory acquisition, short-term, and long-term memory in the novel object recognition test and during auditory processing and mismatch negativity (MMN) and examined the effects of sPCP and sPCP followed by risperidone. We found that the information about the familiar object and its short-term storage were associated with mPFC→dHPC high gamma connectivity (phase slope index) whereas long-term memory retrieval depended on dHPC→mPFC theta connectivity. sPCP impaired short-term and long-term memories, which were associated with increased theta power in the mPFC, decreased gamma power and theta-gamma coupling in the dHPC, and disrupted mPFC-dHPC connectivity. Risperidone rescued the memory deficits and partly restored hippocampal desynchronization but did not ameliorate mPFC and circuit connectivity alterations. sPCP also impaired auditory processing and its neural correlates (evoked potentials and MMN) in the mPFC, which were also partly rescued by risperidone. Our study suggests that the mPFC and the dHPC disconnect during NMDAR hypofunction, possibly underlying cognitive impairment in schizophrenia, and that risperidone targets this circuit to ameliorate cognitive abilities in patients.This study was financed by grants SAF2016-80726-R and PID2019-104683RB-I00 to MVP funded by MCIN/AEI/10.13039/501100011033 and by ERDF “A way of making Europe”. CD-S was supported by a FI AGAUR predoctoral fellowship from the Catalan Government (Generalitat de Catalunya grant number 2018 FI_B_00112)

Atypical, but not typical, antipsychotic drugs reduce hypersynchronized prefrontal-hippocampal circuits during psychosis-like states in mice: contribution of 5-HT2A and 5-HT1A receptors

Data de publicació electrónica: 07-12-2021Neural synchrony and functional connectivity are disrupted in schizophrenia. We investigated changes in prefrontal-hippocampal neural dynamics during psychosis-like states induced by the NMDAR antagonist phencyclidine and subsequent rescue by two atypical antipsychotic drugs (AAPDs), risperidone and clozapine, and the classical APD haloperidol. The psychotomimetic effects of phencyclidine were associated with prefrontal hypersynchronization, hippocampal desynchronization, and disrupted circuit connectivity. Phencyclidine boosted prefrontal oscillatory power at atypical bands within delta, gamma, and high frequency ranges, while irregular cross-frequency and spike-LFP coupling emerged. In the hippocampus, phencyclidine enhanced delta rhythms but suppressed theta oscillations, theta-gamma coupling, and theta-beta spike-LFP coupling. Baseline interregional theta-gamma coupling, theta phase coherence, and hippocampus-to-cortex theta signals were redirected to delta frequencies. Risperidone and clozapine, but not haloperidol, reduced phencyclidine-induced prefrontal and cortical-hippocampal hypersynchrony. None of the substances restored hippocampal and circuit desynchronization. These results suggest that AAPDs, but not typical APDs, target prefrontal-hippocampal pathways to elicit antipsychotic action. We investigated whether the affinity of AAPDs for serotonin receptors could explain their distinct effects. Serotonin 5-HT2AR antagonism by M100907 and 5-HT1AR agonism by 8-OH-DPAT reduced prefrontal hypersynchronization. Our results point to fundamentally different neural mechanisms underlying the action of atypical versus typical APDs with selective contribution of serotonin receptors

Serotonin 5-HT 1A, 5-HT 2A and dopamine D 2 receptors strongly influence prefronto-hippocampal neural networks in alert mice: contribution to the actions of risperidone

Atypical antipsychotic drugs (APDs) used to treat positive and negative symptoms in schizophrenia block serotonin receptors 5-HT2AR and dopamine receptors D2R and stimulate 5-HT1AR 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-HT1AR, 5-HT2AR and D2R 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-HT1AR antagonist WAY-100635, risperidone + 5-HT2A/2CR agonist DOI, risperidone + D2R agonist quinpirole). Risperidone, 5-HT1AR agonism with 8-OH-DPAT, 5-HT2AR antagonism with M100907, and D2R 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-HT2AR 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-HT1AR agonism and 5-HT2AR antagonism in risperidone-induced alterations of delta, beta and gamma oscillations, while D2R 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.This work was supported by the Brain and Behavior Research Foundation (NARSAD Young Investigator Award 23014), SAF2013-49129-C2-2-R and SAF2016-80726-R (AEI / FEDER, UE) by the Spanish Ministry of Economy and Competitiveness (MINECO; to MVP). M.V. Puig is a Ramon y Cajal Investigator (RyC-2012-10042), M. Alemany a FPI predoctoral fellow (BES-2014-070429) from MINECO, and C. Delgado a FI predoctoral fellow (2018FI_B_00112)from the Generalitat de Catalunya (AGAUR