Presynaptic GABAB receptor–mediated network excitation in the medial prefrontal cortex of Tsc2+/- mice

AbstractThe TSC1 and TSC2 tumor suppressor genes control the activity of mechanistic target of rapamycin (mTOR) pathway. Elevated activity of this pathway in Tsc2+/- mouse model leads to reduction of postsynaptic GABAB receptor–mediated inhibition and hyperexcitability in the medial prefrontal cortex (mPFC). In this study, we asked whether presynaptic GABAB receptors (GABABRs) can compensate this shift of hyperexcitability. Experiments were performed in brain slices from adolescent wild-type (WT) and Tsc2+/- mice. Miniature and spontaneous postsynaptic currents (m/sPSCs) were recorded from layer 2/3 pyramidal neurons in mPFC using patch-clamp technique using a Cs+-based intrapipette solution. Presynaptic GABABRs were activated by baclofen (10 µM) or blocked by CGP55845 (1 µM). Independent on genotype, GABABR modulators bidirectionally change miniature excitatory postsynaptic current (mEPSC) frequency by about 10%, indicating presynaptic GABABR-mediated effects on glutamatergic transmission are comparable in both genotypes. In contrast, frequencies of both mIPSCs and sIPCSs were suppressed by baclofen stronger in Tsc2+/- neurons than in WT ones, whereas CGP55845 significantly increased (m/s)IPSC frequencies only in WT cells. Effects of baclofen and CGP55845 on the amplitudes of evoked (e)IPSCs confirmed these observations. These data indicate (1) that GABAergic synapses are inhibited by ambient GABA in WT but not in Tsc2+/- slices, and (2) that baclofen shifts the E/I ratio, determined as the ratio of (m/s)EPSC frequency to (m/s)IPSC frequency, towards excitation only in Tsc2+/- cells. This excitatory presynaptic GABABR-mediated action has to be taken into account for a possible medication of mental disorders using baclofen. Graphical abstract

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Haploinsufficiency of Tsc2 Leads to Hyperexcitability of Medial Prefrontal Cortex via Weakening of Tonic GABAB Receptor-mediated Inhibition

Cerebral Cortex ◽

10.1093/cercor/bhaa187 ◽

2020 ◽

Vol 30 (12) ◽

pp. 6313-6324

Author(s):

Davide Bassetti ◽

Aniello Lombardi ◽

Sergei Kirischuk ◽

Heiko J Luhmann

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Tumor Suppressor Genes ◽

Time Window ◽

Gabab Receptor ◽

Brain Slices ◽

Autism Spectrum ◽

Loss Of Function ◽

Electrophysiological Recordings ◽

Spectrum Disorders

Abstract Loss-of-function mutation in one of the tumor suppressor genes TSC1 or TSC2 is associated with several neurological and psychiatric diseases, including autism spectrum disorders (ASDs). As an imbalance between excitatory and inhibitory neurotransmission, E/I ratio is believed to contribute to the development of these disorders, we investigated synaptic transmission during the first postnatal month using the Tsc2+/− mouse model. Electrophysiological recordings were performed in acute brain slices of medial prefrontal cortex. E/I ratio at postnatal day (P) 15–19 is increased in Tsc2+/− mice as compared with wildtype (WT). At P25–30, facilitated GABAergic transmission reduces E/I ratio to the WT level, but weakening of tonic GABAB receptor (GABABR)-mediated inhibition in Tsc2+/− mice leads to hyperexcitability both at single cell and neuronal network level. Short (1 h) preincubation of P25–30 Tsc2+/− slices with baclofen restores the GABABR-mediated inhibition and reduces network excitability. Interestingly, the same treatment at P15–19 leads to weakening of GABABR-mediated inhibition. We hypothesize that a dysfunction of tonic GABABR-mediated inhibition might contribute to the development of ASD symptoms and suggest that GABABR activation within an appropriate time window may be considered as a therapeutic target in ASD.

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β1- and β2-Adrenergic activations enhance excitatory synaptic transmission in layer V/VI pyramidal neurons of the medial prefrontal cortex of rats

Neuroscience Research ◽

10.1016/j.neures.2010.07.1989 ◽

2010 ◽

Vol 68 ◽

pp. e449

Author(s):

Zejun Feng

Keyword(s):

Prefrontal Cortex ◽

Synaptic Transmission ◽

Medial Prefrontal Cortex ◽

Pyramidal Neurons ◽

Excitatory Synaptic Transmission ◽

Layer V

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Developmental Regulation of Basket Interneuron Synapses and Behavior through NCAM in Mouse Prefrontal Cortex

Cerebral Cortex ◽

10.1093/cercor/bhaa074 ◽

2020 ◽

Vol 30 (8) ◽

pp. 4689-4707

Author(s):

Chelsea S Sullivan ◽

Vishwa Mohan ◽

Paul B Manis ◽

Sheryl S Moy ◽

Young Truong ◽

...

Keyword(s):

Prefrontal Cortex ◽

Pyramidal Neurons ◽

Developmental Regulation ◽

Brain Slices ◽

Pyramidal Cells ◽

Electrophysiological Recording ◽

Network Function ◽

Growth Cone Collapse ◽

Layer 2 ◽

And Behavior

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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