Investigating effects of Ampakines in cortical neurons, - implications for cognitive enhancement and brain doping

The dysfunction of glutamatergic receptors, particularly α-amino-3-hydroxyl-5-methyl-4-isoxazepolepropoanic acid (AMPA) receptors, has been observed in a broad spectrum of neurological diseases ranging from dementia to schizophrenia. The involvement of AMPA receptors in several disorders explains their attention in the pharmaceutical industry. Positive allosteric modulators, termed Ampakines, have been synthesised based on the hypothesis that synaptic receptors could be modulated to alleviate cognitive deficits present in disease. In this study, utilizing electrophysiological recordings the Ampakines CX614 and CMPDA were used to test whether they modulate synaptic transmission in two different types of neurons, excitatory pyramidal neurons and GABAergic NDNF (Neuron-derived neurotrophic factor)-positive neurons, in the medial prefrontal cortex (mPFC), an area of the brain associated with cognitive ability. NDNF-positive neurons were identified unambiguously in transgenic mice expressing fluorescent protein under the control of the NDNF promoter. Spontaneous excitatory post-synaptic currents (sEPSC) were recorded before and after the application of CX614 andCMPDA. CX614 increased the frequency, as well as tau and the half duration of the sEPSCs in layer 2/3 cortical pyramidal neurons. The decay time constant tau, however, was the only measured parameter found to be significantly enhanced in NDNF-expressing interneurons located in superficial layers of the mPFC. The amplitude of sEPSCs was inconsistently increased in both cell types. Intriguingly, it has been shown that Ampakines do not only demonstrate an AMPA receptor subunit selectively, but also show different efficacy depending on the AMPA receptor auxiliary subunit expression. The data suggests that non-responding neurons may either lack specific AMPA receptor subunits or AMPA receptor auxiliary subunits preferentially modulated by Ampakines. It is concluded that CX614 has a more potent effect on AMPA receptor-mediated synaptic transmission in pyramidal neurons compared to NDNF-expressing interneurons in the mPFC. Future studies testing Ampakines should pair electrophysiological recordings with a sophisticated analysis of expression pattern of both AMPA receptor subunits and auxiliary subunits of the AMPA receptor.The dysfunction of glutamatergic receptors, particularly α-amino-3-hydroxyl-5-methyl-4-isoxazepolepropoanic acid (AMPA) receptors, has been observed in a broad spectrum of neurological diseases ranging from dementia to schizophrenia. The involvement of AMPA receptors in several disorders explains their attention in the pharmaceutical industry. Positive allosteric modulators, termed Ampakines, have been synthesised based on the hypothesis that synaptic receptors could be modulated to alleviate cognitive deficits present in disease. In this study, utilizing electrophysiological recordings the Ampakines CX614 and CMPDA were used to test whether they modulate synaptic transmission in two different types of neurons, excitatory pyramidal neurons and GABAergic NDNF (Neuron-derived neurotrophic factor)-positive neurons, in the medial prefrontal cortex (mPFC), an area of the brain associated with cognitive ability. NDNF-positive neurons were identified unambiguously in transgenic mice expressing fluorescent protein under the control of the NDNF promoter. Spontaneous excitatory post-synaptic currents (sEPSC) were recorded before and after the application of CX614 andCMPDA. CX614 increased the frequency, as well as tau and the half duration of the sEPSCs in layer 2/3 cortical pyramidal neurons. The decay time constant tau, however, was the only measured parameter found to be significantly enhanced in NDNF-expressing interneurons located in superficial layers of the mPFC. The amplitude of sEPSCs was inconsistently increased in both cell types. Intriguingly, it has been shown that Ampakines do not only demonstrate an AMPA receptor subunit selectively, but also show different efficacy depending on the AMPA receptor auxiliary subunit expression. The data suggests that non-responding neurons may either lack specific AMPA receptor subunits or AMPA receptor auxiliary subunits preferentially modulated by Ampakines. It is concluded that CX614 has a more potent effect on AMPA receptor-mediated synaptic transmission in pyramidal neurons compared to NDNF-expressing interneurons in the mPFC. Future studies testing Ampakines should pair electrophysiological recordings with a sophisticated analysis of expression pattern of both AMPA receptor subunits and auxiliary subunits of the AMPA receptor