Developmental regulation of excitatory-inhibitory synaptic balance in the prefrontal cortex during adolescence

Abstract Parvalbumin (PV)-expressing basket interneurons in the prefrontal cortex (PFC) regulate pyramidal cell firing, synchrony, and network oscillations. Yet, it is unclear how their perisomatic inputs to pyramidal neurons are integrated into neural circuitry and adjusted postnatally. Neural cell adhesion molecule NCAM is expressed in a variety of cells in the PFC and cooperates with EphrinA/EphAs to regulate inhibitory synapse density. Here, analysis of a novel parvalbumin (PV)-Cre: NCAM F/F mouse mutant revealed that NCAM functions presynaptically in PV+ basket interneurons to regulate postnatal elimination of perisomatic synapses. Mutant mice exhibited an increased density of PV+ perisomatic puncta in PFC layer 2/3, while live imaging in mutant brain slices revealed fewer puncta that were dynamically eliminated. Furthermore, EphrinA5-induced growth cone collapse in PV+ interneurons in culture depended on NCAM expression. Electrophysiological recording from layer 2/3 pyramidal cells in mutant PFC slices showed a slower rise time of inhibitory synaptic currents. PV-Cre: NCAM F/F mice exhibited impairments in working memory and social behavior that may be impacted by altered PFC circuitry. These findings suggest that the density of perisomatic synapses of PV+ basket interneurons is regulated postnatally by NCAM, likely through EphrinA-dependent elimination, which is important for appropriate PFC network function and behavior.

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Prolonged Exposure to NMDAR Antagonist Suppresses Inhibitory Synaptic Transmission in Prefrontal Cortex

Journal of Neurophysiology ◽

10.1152/jn.00079.2008 ◽

2008 ◽

Vol 100 (2) ◽

pp. 959-965 ◽

Cited By ~ 67

Author(s):

Yuchun Zhang ◽

M. Margarita Behrens ◽

John E. Lisman

Keyword(s):

Prefrontal Cortex ◽

Prolonged Exposure ◽

Developmental Regulation ◽

Gamma Oscillations ◽

Acid Decarboxylase ◽

Aspartate Receptor ◽

Functional Inhibition ◽

Key Enzyme ◽

Gaba Synthesis ◽

Postmortem Studies

Postmortem studies have shown that schizophrenia produces a reduction in the 67-kilodalton isoform of glutamic acid decarboxylase (GAD67), a key enzyme for γ-aminobutyric acid (GABA) synthesis. N-methyl-d-aspartate receptor (NMDAR) antagonists have been extensively used to study schizophrenia because they can induce many aspects of the disease, including the decrease in GAD67. It is generally thought that this reduction in GAD implies a reduction in functional inhibition, but direct evidence had been lacking. We have therefore performed physiological studies in slices of prefrontal cortex taken from rats treated with the NMDAR antagonist ketamine. Both frequency and amplitude of miniature inhibitory postsynaptic currents were reduced. Consistent with a reduction of inhibition, we observed an increase in postsynaptic excitability. The increased excitability is likely to result from disinhibition because miniature excitatory postsynaptic current properties and intrinsic excitability were not changed. Ketamine did not affect inhibition or GAD levels in young rats, indicating a developmental regulation that may be related to the developmental increase in ketamine sensitivity that occurs in humans. Our results show that NMDAR antagonist produces biochemical changes in the GABA system that lead to a functional disinhibition. Such disinhibition would be expected to decrease gamma oscillations, which are reduced in schizophrenia.

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