Neocortical network activity is generated through a dynamic balance between excitation, provided by pyramidal neurons, and inhibition, provided by interneurons. Imbalance of the excitation/inhibition ratio has been identified in several neuropsychiatric diseases, such as schizophrenia, autism and epilepsy, which also present with other cognitive deficits and symptoms associated with prefrontal cortical (PFC) dysfunction. We undertook a computational approach to study how changes in the excitation/inhibition balance in a PFC microcircuit model affect the properties of persistent activity, considered the cellular correlate of working memory function in PFC. To this end, we constructed a PFC microcircuit, consisting of pyramidal neuron models and all three different interneuron types: fast-spiking (FS), regular-spiking (RS), and irregular-spiking (IS) interneurons. Persistent activity was induced in the microcircuit model with a stimulus to the proximal apical dendrites of the pyramidal neuron models, and its properties were analyzed, such as the induction profile, the interspike intervals (ISIs) and neuronal synchronicity. Our simulations showed that (a) the induction but not the firing frequency or neuronal synchronicity is modulated by changes in the NMDA-to-AMPA ratio on FS interneuron model, (b) removing or decreasing the FS model input to the pyramidal neuron models greatly limited the biophysical modulation of persistent activity induction, decreased the ISIs and neuronal synchronicity during persistent activity, (c) the induction and firing properties could not be altered by the addition of other inhibitory inputs to the soma (from RS or IS models), and (d) the synchronicity change could be reversed by the addition of other inhibitory inputs to the soma, but beyond the levels of the control network. Thus, generic somatic inhibition acts as a pacemaker of persistent activity and FS specific inhibition modulates the output of the pacemaker.

Schizophrenia is a debilitating disorder with complex and unclarified etiological factors. Sex differences have been observed in humans but animal models have only focused on male subjects. In this study, we report the establishment of the neurodevelopmental MAM model of schizophrenia in mice and compare the schizotypic-like characteristics and cognitive function in both sexes. Pregnant mice were injected with 26mg/kg(i.p.) of Methylazoxy-methanol acetate (MAM) or saline (5ml/kg) on gestational day (GD) 16 (MAM-16) or 17 (MAM-17). Behavioral, histological and electrophysiological and mass spectrometry-based comparative proteomic techniques were employed to assess the schizotypic-like characteristics and cognitive function of adult male and female offspring (MAM-or saline-treated). Female MAM-16, but not MAM-17 treated mice exhibited enhanced hyperlocomotion after acute administration of the NMDA receptor antagonist, MK-801, compared to saline treated mice. Male MAM-16, but not MAM-17 treated mice showed decreased pre-pulse inhibition of the acoustic startle reflex. Both male and female MAM-16 and MAM-17 treated mice exhibited reduced hippocampal (HPC) size and thinning of the prefrontal cortex (PFC), but only male MAM-16 treated mice showed decreased parvalbumin expression in HPC and PFC. Similarly, both male and female MAM-16 treated mice displayed impaired contextual fear memory, while only male MAM-16 treated mice exhibited deficits in the delayed alternation task. The neurophysiological mechanisms that underlie these cognitive functions were further investigated. Both male and female MAM-16 treated mice had significantly reduced long-term potentiation (LTP) in the HPC CA1 synapses, while only male MAM-16 treated mice exhibited decreased LTP in the PFC. Proteomic analyses of PFC lysates further showed significant MAM-and sex-dependent differences in regulation . CC-BY-NC-ND 4.

Although circadian and sleep disorders are frequently associated with autism spectrum disorders (ASD), it remains elusive whether clock gene disruption can lead to autistic-like phenotypes in animals. The essential clock gene Bmal1 has been associated with human sociability and its missense mutations are identified in ASD. Here we report that global Bmal1 deletion led to significant social impairments, excessive stereotyped and repetitive behaviors, as well as motor learning disabilities in mice, all of which resemble core behavioral deficits in ASD. Furthermore, aberrant cell density and immature morphology of dendritic spines were identified in the cerebellar Purkinje cells (PCs) of Bmal1 knockout (KO) mice. Electrophysiological recordings uncovered enhanced excitatory and inhibitory synaptic transmission and reduced firing rates in the PCs of Bmal1 KO mice. Differential expression of ASD- and ataxia-associated genes ( Ntng2 , Mfrp , Nr4a2 , Thbs1 , Atxn1 , and Atxn3 ) and dysregulated pathways of translational control, including hyperactivated mammalian target of rapamycin complex 1 (mTORC1) signaling, were identified in the cerebellum of Bmal1 KO mice. Interestingly, the antidiabetic drug metformin reversed mTORC1 hyperactivation and alleviated major behavioral and PC deficits in Bmal1 KO mice. Importantly, conditional Bmal1 deletion only in cerebellar PCs was sufficient to recapitulate autistic-like behavioral and cellular changes akin to those identified in Bmal1 KO mice. Together, these results unveil a previously unidentified role for Bmal1 disruption in cerebellar dysfunction and autistic-like behaviors. Our findings provide experimental evidence supporting a putative role for dysregulation of circadian clock gene expression in the pathogenesis of ASD.

Adolescence is a highly vulnerable period for the emergence of major neuropsychological disorders and is characterized by decreased cognitive control and increased risk-taking behavior and novelty-seeking. The prefrontal cortex (PFC) is involved in the cognitive control of impulsive and risky behavior. Although the PFC is known to reach maturation later than other cortical areas, little information is available regarding the functional changes from adolescence to adulthood in PFC, particularly compared with other primary cortical areas. This study aims to understand the development of PFC-mediated, compared with non-PFC-mediated, cognitive functions. Toward this aim, we performed cognitive behavioral tasks in adolescent and adult mice and subsequently investigated synaptic plasticity in two different cortical areas. Our results showed that adolescent mice exhibit impaired performance in PFC-dependent cognitive tasks compared with adult mice, whereas their performance in non-PFC-dependent tasks is similar to that of adults. Furthermore, adolescent mice exhibited decreased long-term potentiation (LTP) within upper-layer synapses of the PFC but not the barrel cortex. Blocking GABA receptor function significantly augments LTP in both the adolescent and adult PFC. No change in intrinsic excitability of PFC pyramidal neurons was observed between adolescent and adult mice. Finally, increased expression of the NR2A subunit of the N-methyl-d-aspartate receptors is found only in the adult PFC, a change that could underlie the emergence of LTP. In conclusion, our results demonstrate physiological and behavioral changes during adolescence that are specific to the PFC and could underlie the reduced cognitive control in adolescents. NEW & NOTEWORTHY This study reports that adolescent mice exhibit impaired performance in cognitive functions dependent on the prefrontal cortex but not in cognitive functions dependent on other cortical regions. The current results propose reduced synaptic plasticity in the upper layers of the prefrontal cortex as a cellular correlate of this weakened cognitive function. This decreased synaptic plasticity is due to reduced N-methyl-d-aspartate receptor expression but not due to dampened intrinsic excitability or enhanced GABAergic signaling during adolescence.