Perineuronal nets in cognition and behaviour

Perineuronal nets (PNNs) are extracellular matrix structures surrounding neurons in the mammalian central nervous system1. PNNs have been implicated in limiting neuronal plasticity outside critical developmental periods and, in some brain regions, PNN removal in adulthood facilitates neuronal plasticity and associated memory functions1-3. On the other hand, PNN disruptions in several brain regions characterise some neuropsychiatric disorders, including schizophrenia1,4,5, and PNN removal in selected brain regions in rodents also impairs some cognitive and behavioural functions 6-8.
In neocortex and hippocampus, PNNs mainly surround GABAergic inhibitory interneurons and have been implicated in maintenance and regulation of GABAergic inhibition, suggesting that PNN disruption may disrupt GABAergic inhibition1,3,4,9,10. This is of clinical relevance, because impaired GABAergic inhibition, including in prefrontal cortex and hippocampus, is a key feature of schizophrenia, and disruption of GABAergic inhibition, so-called neural disinhibition, in these brain regions causes clinically relevant cognitive and behavioural deficits in rats11. However, it largely remains to be examined if PNN disruption in prefrontal cortex and hippocampus causes similar deficits to neural disinhibition.

Moreover, many rodent models based on factors implicated in schizophrenia pathophysiology, including NMDA receptor hypofunction, show disruption of both PNNs and GABAergic interneurons, particularly in prefrontal cortex and hippocampus6,12-15. However, although the NMDA receptor hypofunction model involving subchronic injections of the NMDA receptor antagonist phencyclidine is widely used in basic and drug discovery research14, PNN disruption in this model has not been characterised; in addition, the relationship between NMDA receptor hypofunction, PNN and GABAergic interneuron disruption, and clinically relevant cognitive and behavioural impairments largely remains to be determined.

AIMS AND RESEARCH PLAN

The student will study how PNNs in prefrontal cortex and hippocampus contribute to cognition and behaviour in rats. The project will use brain site-specific manipulations of PNNs (Aim 1) and the subchronic phencyclidine model of NMDA receptor hypofunction (Aim 2) in combination with behavioural tests, in vivo electrophysiology and ex vivo histological methods.

Aim 1: We will study if PNNs are required for some of the neural, behavioural and cognitive functions we have shown to require prefrontal and hippocampal GABAergic inhibition11,16-19. To this end, we will use removal of PNNs in prefrontal cortex or hippocampus by local injection of the enzyme chondroitinase ABC2,3,6-8, in combination with in vivo electrophysiological measurements and behavioural testing in rats, similar to our previous studies16-19. Using ex vivo histological methods20,21, we will also examine if PNN removal disrupts GABAergic interneuron markers (including GAD67 and calcium-binding proteins parvalbumin, calbindin and calretinin).

Aim 2: Using ex vivo histological methods20,21, we will characterise PNN disruption in prefrontal cortex and hippocampus of the subchronic phencyclidine model of NMDA receptor hypofunction14 and examine if PNN changes are associated with the disruption of GABAergic interneuron markers in this model. We will also correlate histological measures with cognitive and behavioural impairments in the model, as well as to the rescue of such impairments by scheduled exercise.