Fear extinction disruption in a developmental rodent model of schizophrenia correlates with an impairment in basolateral amygdala-medial prefrontal cortex plasticity

Abstract

Schizophrenia patients typically exhibit prominent negative symptoms associated with deficits in extinction recall and decreased ventromedial prefrontal cortex activity (vmPFC, analogous to medial PFC infralimbic segment in rodents). mPFC activity modulates the activity of basolateral amygdala (BLA) and this connectivity is related to extinction. mPFC and BLA activity has been shown to be altered in the methylazoxymethanol acetate (MAM) developmental disruption model of schizophrenia. However, it is unknown if there are alterations in extinction processes in this model. Therefore, we investigated extinction and the role of mPFC-BLA balance in MAM rats. Male offspring of pregnant rats treated with Saline or MAM (20 mg/kg; i.p.) on gestational day 17 were used in fear conditioning (contextual/tone) and electrophysiological experiments (mPFC-BLA plasticity). No difference was observed in conditioning, extinction, and test sessions in contextual fear conditioning. However, MAM-treated rats demonstrated impairment in extinction learning and recall in tone fear conditioning. Furthermore, high frequency stimulation (HFS) of the BLA decreased spike probability in the mPFC of saline-treated rats but not in MAM rats. NMDA antagonist microinjected into the BLA disrupted extinction learning and recall in control rats, resulting in a similar deficit as that observed in MAM-treated rats. These data demonstrate extinction impairment in the MAM model that is analogous to that observed in schizophrenia patients, that was probably due to disruption in the regulation of mPFC activity by glutamatergic neurotransmission in the BLA.

Amygdala subdivisions exhibit aberrant whole-brain functional connectivity in relation to stress intolerance and psychotic symptoms in 22q11.2DS

“…Dense reciprocal connections between BLA and hippocampus have been previously identified. Notably, impairment of the interconnected circuit between mPFC, hippocampus and BLA had been implicated in anxiety-like behavior (80)(81)(82)(83). Our multivariate results point to higher BLA-hippocampus functional connectivity that cooccurs with lower BLA-PFC functional connectivity in patients with 22q11.2DS.…”

Aberrant Gray Matter Volume and Cortical Surface in Paranoid-Type Delusional Disorder

“…Abnormal structure and function of lateral PFC, frequently associated with aberrant executive functioning [58,59] and related belief evaluation deficits [25][26][27] are common findings in both DD and SZ patients. Further, a disruption of fear extinction has been found to be associated with altered connectivity between the amygdala and PFC [60][61][62]. In line with this, aberrant PFC and amygdala coupling in DD may be associated with impaired extinction of fear and anxiety, which, in turn, may facilitate the development and persistence of threat.…”

Genome-wide association study detected novel susceptibility genes for social cognition impairment in people with schizophrenia

“…Moreover, a dysregulation in the activity of BLA nucleus has been suggested to have a clear implication in the etiopathogenesis of social dysfunction in ASD (Ferri et al 2016;Hennessey et al 2018). Furthermore, preliminary studies have demonstrated that neuroarchitectural changes occur in the BLA nucleus of persons with SCZ (Williams et al 2016) while dysregulation in functioning of BLA nucleus strongly correlated with a heightened stress and fear sensitivity to sensory inputs (a characteristic often observed in SCZ) in a developmental rodent model of SCZ (Uliana et al 2018). Therefore, it could be hypothesised that some variants in the TMEM74 gene identified in our study influence the brain expression of this gene, altering the functionality of the BLA nucleus and consequently increasing the probability of having a dysfunctional social behaviour.…”