From Shortage to Surge: A Developmental Switch in Hippocampal–Prefrontal Coupling in a Gene–Environment Model of Neuropsychiatric Disorders

Abstract

Cognitive deficits represent a major burden of neuropsychiatric disorders and result in part from abnormal communication within hippocampal–prefrontal circuits. While it has been hypothesized that this network dysfunction arises during development, long before the first clinical symptoms, experimental evidence is still missing. Here, we show that pre-juvenile mice mimicking genetic and environmental risk factors of disease (dual-hit GE mice) have poorer recognition memory that correlates with augmented coupling by synchrony and stronger directed interactions between prefrontal cortex and hippocampus. The network dysfunction emerges already during neonatal development, yet it initially consists in a diminished hippocampal theta drive and consequently, a weaker and disorganized entrainment of local prefrontal circuits in discontinuous oscillatory activity in dual-hit GE mice when compared with controls. Thus, impaired maturation of functional communication within hippocampal–prefrontal networks switching from hypo- to hyper-coupling may represent a mechanism underlying the pathophysiology of cognitive deficits in neuropsychiatric disorders.

Theta Oscillations during Active Sleep Synchronize the Developing Rubro-Hippocampal Sensorimotor Network

“…As recently shown in the hippocampal-prefrontal system in a mouse model of schizophrenia, abnormal connectivity was detected very early in development before cognitive deficits were apparent [79]. In a similar vein, the current findings suggest that impaired functional connectivity in the rubro-hippocampal network may predict and contribute to sensorimotor deficits; such impairments could be caused by a number of factors, including sleep disruption.…”

Developmental dysfunction of prefrontal–hippocampal networks in mouse models of mental illness

“…However, the oscillatory properties differed between groups (occurrence: F 7 , 111 = 4.89, p < 0.001; duration: F 7 , 111 = 3.77, p < 0.001; Figure b(i) and (ii), Table ). In line with our previous findings (Hartung et al., ), the prelimbic activity of DISC1 + MIA mice appeared highly fragmented and correspondingly, the occurrence of oscillatory events was higher ( p = 0.01) when compared with controls. In contrast, the oscillatory activity in PL of one‐hit DISC1 and MIA mice was not affected.…”

“…Specifically, the dysfunction of local and long‐range circuits centred on PFC correlate with decreased working memory, prepulse inhibition, sociability, and spatial recognition memory as well as increased depression‐like behaviour (Clapcote et al., ; Niwa et al., ; Sauer, Strüber, & Bartos, ). However, in line with our past (Hartung et al., ) and present results, the genetic abnormality is not sufficient for disrupting the initial entrainment of neonatal prefrontal–hippocampal circuits in oscillatory rhythms.…”

“…These structural and functional deficits may perturb the prelimbic activity and initial wiring of local circuits. Structural changes in PL, such as decrease in spine density or lower number of axonal terminals, might lead to decreased firing of pyramidal neurons in PL (Xu et al., ), but also to loss of theta‐timed precision of firing, as reflected by the weaker strength of theta‐spike coupling (Hartung et al., ). These results are in line with previous data reported for adult dual‐hit DISC1‐MIA mice that show decreased spine density on hippocampal neurons as well as decreased sociability and augmented anxiety and depressive‐like behaviour (Abazyan et al., ).…”

Active Sleep Promotes Functional Connectivity in Developing Sensorimotor Networks

“…Aberrant network connectivity can be detected very early in development and appears to presage cognitive and sensorimotor impairments . In humans, atypical connectivity patterns are present in individuals diagnosed with ADHD, autism, and schizophrenia…”